Drugs and Pharmaceuticals

Current R & D Highlights

(Organometallic Compounds in  Drug Research)











·     Organometallic Compounds in  Drug Research                                                               1



·     Exploring Biologically Relevant

      Chemical Space with Metal Complexes        2

·     Current Applications and Future Potential

     for Bioinorganic Chemistry in the

     Development of Anticancer Drugs                7


News & Views                                          15


R&D Highlights                                       21


R& D Technology

·     Organometallic Compounds in Oncology: Implications of Novel Organotins

     as Antitumor Agents                                                39


New Leads                                               50


Natural Products                                 54


Biotechnology                                       55


Patents                                                 56










Organometallic Compounds  in Drug Research


       Organometallic Compounds have been used in medicine for centuries, but often in an empirical way with little attempt to design the compound to be used and with little understanding of the molecular basis of their mechanism of action. The discovery and development of the antitumor compound –cisplatin, world’s best selling anticancer drug, played profound role in establishing the field of medicinal inorganic chemistry. Over the past decades several cisplatin analogues have been screened as potential antitumor agents, but of these only two carboplatin and oxaliplatin have entered worldwide clinical use.

       In addition to platinum compounds, other metal-based compounds in clinical use include auranofin (gold), lithium carbonate, gadolinium complexes and 99Tc complexes, etc.

       A characteristic of metals is that they easily lose electrons from elemental or metallic state to form positively charged ion which tend to be soluble in biological fluids. It is in this cationic form that metals play their role in biology. Whereas metal ions are electron deficient, most biological molecules such as proteins and DNA are electron rich. The attraction of these opposing charges leads to a general tendancy for metal ions to bind to and interact with biological molecules. The same principal applies to the affinity of metal ions for many small molecules and ions crucial for life, such as O2. Hemoglobin is an iron- containing protein that binds to oxygen through its iron atom, transports this vital molecule to body tissues. Thus metals, such as, copper, zinc, iron and manganese are incorporated into metalloenzymes—which facilitate a multitude of chemical reaction needed for life.

       Metal coordination to biologically active molecules can be used as strategy to enhance their activity and overcome resistance. Pd (II) and Pt (II) complexes with antibiotics of tetracycline family are more potent against E.coli HB101/pBR322, a bacterial strain resistant to tetracycline.

       Carbon the most important element in the drug design, can generate inert covalent bonds with connectivities of two to four, and with bonding geometries about the carbon atom that range from linear to trigonal planar to tetrahedral. This has nevertheless allowed for a incredible number of different molecules to be prepared based on carbon, despite the fact that binding geometries obtainable are fairly limited. By contrast, metal ions can create either labile or inert bonds with coordination numbers ranging from one to twelve, and with numerous geometries including linear, trigonal planar, tetrahedral, octahedral and many others. This simple comparision suggests that metal ions can be used as new scaffolds about which one can construct therapeutic molecules that achieve shapes and structures that would be impossible or extremely difficult to achieve with carbon-based compounds.

-----Sheela Tandon








Exploring Biologically Relevant Chemical Space with MetalComplexes



       The identification of compounds with novel and defined biological functions is of high importance for research in medicinal chemistry and chemical biology. The total number of theoretically accessible compounds with biological activity span the ‘biologically relevant chemical space’. Charting this subset of the chemical space is focused primarily on small organic molecules. In this respect one might wonder whether organic-based scaffolds are capable of covering all areas of the biologically relevant chemical space in an efficient fashion. To address this question, it is interesting to explore the opportunities of inorganic elements to help build small compounds with defined three-dimensional structures. Transition metals appear especially appealing for this purpose because they can support a multitude of coordination numbers and geometries that go far beyond the linear (sp-hybridization), trigonal planar (sp2-hybridization) and tetrahedral (sp3-hybridization) binding geometries of carbon (Figure 1). For example, it is intriguing that an octahedral center with six different substituents is capable of forming 30 stereoisomers compared with just two for an asymmetric tetrahedral carbon. Thus, by increasing the number of substituents from four (tetrahedral center) to six (octahedral center), the ability of the center to organize substituents in the three-dimensional space increases substantially. In addition, using a hexavalent center could provide new synthetic opportunities for accessing globular shapes by building structures from a single center in six different directions. Inorganic pharmaceuticals play an important role in clinical therapy (e.g. cisplatin) and diagnostics (e.g. MRI contrast agents). For these classes of inorganic compounds the coordination chemistry itself is at the heart of the mode of action. This short review is limited to past and current research activities that aim to design metal complexes with biological activities in which the metal center mainly serves as a structural center for organizing the presentation of organic ligands at the binding site of protein targets.








Figure 1. Transition metals provide an expanded set of coordination geometries

for the generation of molecular diversity.

       More than half a century ago, the Australian chemist Francis Dwyer started to investigate the biological activities of simple coordination complexes such as ruthenium complexes with 2, 2′-bipyridine and 1,10-phenanthroline (phen) ligands. He discovered that some very hydrophobic complexes (e.g.Figure 2a) displayed bacteriostatic and bacteriocidal activities and were capable of inhibiting tumor growth in a mouse xenograph model. Interestingly, fluorescence microscopy studies demonstrated that these dicationic ruthenium complexes were able to pass the cellular membrane and were found to localize in the mitochondria. The ruthenium complexes also caused paralysis and respiratory failure after intraperitoneal (IP) injection into mice at high concentrations, apparently owing to their potent direct inhibition of acetylcholinesterase. Investigations into the biological stability of [Ru(phen)3](ClO4)2] confirmed that the ruthenium complex after IP injection into mice was not metabolized and excreted mainly unchanged in the urine. Because of the coordinative saturation of the coordination sphere, their chemical and biological stabilities, Dwyer drew the following important conclusion: ‘Such doubly charged pre-formed Ru(II) chelates are stable in boiling concentrated acids or alkali and in animal tissues. Hence their biological effects depend solely on the physico-chemical properties of the Ru(II) complex cation as a whole since no ruthenium ion or ligand is liberated’.

Ruthenium Complexes as Protein Kinase Inhibitors

       Following Dwyer's spirit, Meggers and coworkers developed organoruthenium compounds as protein kinase inhibitors. For this, the class of ATP-competitive indolocarbazole alkaloids (e.g. staurosporine) was used as a lead structure. The indolocarbazole alkaloid scaffold was replaced with simple metal complexes in which the main features of the indolocarbazole aglycon are retained in the metal-chelating pyridocarbazole ligand, whereas the carbohydrate is replaced by a ruthenium fragment. Following this design strategy, nanomolar and even subnanomolar ATP-competitive ruthenium-based inhibitors for different protein kinases were discovered (e.g.Figure 2), some of them by combinatorial chemistry and these compounds are air-stable, stable in water, and can even withstand millimolar concentrations of thiols. This stability is due to the inert character of typical coordinative bonds to ruthenium. This, together with the modest price of its starting material RuCl3, its low toxicity, and its predictable and established synthetic chemistry, makes ruthenium possibly the most attractive metal for establishing octahedral or pseudo-octahedral coordination geometries. It was furthermore demonstrated that such ruthenium compounds can function within mammalian cells, Xenopus embryos and zebrafish embryos. Recent cocrystal structures confirm that these compounds bind to the ATP-binding site of protein kinases. For example, shows an organoruthenium half-sandwich complex bound to the ATP-binding site of Pim-1. The ruthenium center is not involved in any direct interactions and has solely a structural role. Furthermore, superposition of the binding positions of cocrystalized ruthenium complex and staurosporine (PDB code 1YHS) with Pim-1 demonstrates how closely the ruthenium complex mimics the binding mode of staurosporine. The pyridocarbazole ligand perfectly mimics the position of the indolocarbazole moiety of staurosporine, whereas the cyclopentadienyl ring and the CO group occupy the binding position of the carbohydrate moiety of staurosporine.























Figure 2. Towards chemical biology with metal complexes. (a)Ruthenium complex with antibacterial and antitumor activity. (b)Nanomolar inhibitors for the protein kinases GSK-3α (left) and MSK1 (right). (c) 1′-Aminoferrocene-1-carboxylic acid induces turns in peptides. (d) A bis(bidentate) rhenium(V) complex mimics the structure of dihydrotestosterone. (e) Organo-metallic estrogen receptor modulator ferrocifen derived from the drug tamoxifen. (f)[Fe (EDTA)(H2O)] binds to the periplasmic nickel transporter NikA.(g) Copper complex as HIV-1 protease inhibitor. (h) AMD3100 binds with high affinity to the CXCR4 coreceptor and this binding is enhanced in the presence of zinc ions


Mimicking the Structure of Natural Products with Metal Complexes

       Whereas the work on metal-based kinase inhibitors used the class of indolocarbazole alkaloids primarily as an inspiration, it is also desirable to mimic the structure and function of natural products more closely to gain more efficient access to a complex three-dimensional structure and to add desired physicochemical properties. The latter is what Katzenellenbogen and coworkers had in mind when they designed rhenium complexes as mimics of the structure of steroid hormones. Steroid receptors are often overexpressed in cancer cells and are therefore a target in the design of radiolabeled small-molecule diagnostics (e.g. Tc-99m) and therapeutics (e.g. Re-186 and Re-188) for cancer detection and treatment, respectively. Katzenellen-bogen's group reported the bis-bidentate oxorhenium(V) complex shown in Figure 2d, which is a remarkable structural and stereochemical mimic of the androgen 5α-dihydrotestosterone (DHT) as can also be seen from the comparison of the two space-filling models in Figure 2d. An exciting aspect of this study is that the metal center fulfils a dual purpose. Unfortunately, the instability of such rhenium compounds with bidentate ligands precludes in vivo applications.

Bioorganometallic Chemistry with Ferrocene

       The organometallic sandwich compound ferrocene is an interesting building block for the design of biologically active molecules because of its unique structure, its robustness in aqueous solutions, and its favorable redox properties. For example, Metzler-Nolte and coworkers incorporated the organometallic amino acid 1′-aminoferrocene-1-carboxylic acid into peptides to induce turns (Figure 2c). In this system, the peptides are arranged in an antiparallel β-sheet-like arrangement stabilized by intramolecular hydrogen bonds. Because turn structures and β-sheets are important recognition motifs in protein–protein interactions, it can by expected that ferrocene serves as an interesting building block for turn-containing peptidomimetics.

       In another application of ferrocene in bio-organometallic chemistry, Jaouen and coworkers developed simple organometallic analogs of tamoxifen. Tamoxifen (Figure 2e) is an antagonist of the estrogen receptor (ER) and widely used in the clinic for the treatment of hormone-dependent breast cancer. The organometallic analog ferrocifen (Figure 2e), which bears an additional hydroxyl group and has one phenyl group replaced by a bulky and hydrophobic ferrocene moiety, exhibits strong antiproliferative effects. It is thought that ferrocifen, in analogy to tamoxifen, suppresses estradiol-mediated DNA transcription by binding to ERα. However, it was recently discovered that ferrocifen displays strong antiproliferative activities both in hormone-dependent (contain ER) and hormone-independent (lack ER) breast cancer cells, indicating a distinguished mode of action. Because the ruthenium derivative does not show the same cytotoxicity profile, it is assumed that the prominent redox properties of ferrocene play an important role. A sequence of oxidation, deprotonation, and further oxidation could generate an electrophile that is capable of damaging DNA or reacting with proteins. Thus, in ferrocifene, the organometallic unit fulfils both a structural and reactive role.

Related Uses of Metal Complexes

       It is apparent that for in vitro and in vivo applications, metal complexes with kinetically inert bonds are highly desirable. However, multidentate ligands such as the hexadentate ligand ethylenediaminetetraacetate (EDTA) can form highly stable complexes even with kinetically very labile metals. Fontecilla-Camps and coworkers found serendipitously that the heptacoordinated pentagonal bipyramidal iron complex [Fe(EDTA) (H2O)]−(Figure 2f) binds tightly to the periplasmic nickel transport protein NikA. A 1.8 Ĺ cocrystal structure is shown in and demonstrates that the complex is bound through a combination of hydrogen bonds, electrostatic, and hydrophobic contacts. Accordingly, carboxylate groups of EDTA hydrogen bond with Arg97 and Arg137 and form three additional water-mediated contacts. This is supplemented by a set of hydrophobic contacts between methylene groups of EDTA and Met27, Tyr22, Trp100, and Trp398. Especially the two tryptophans serve as wedges that complement the shape of the iron EDTA complex. Importantly, the iron does not form any direct coordinative bond with NikA residues and thus has mainly the purpose to organize the structure of the EDTA ligand. However, one can postulate an unshielded cation-π interaction between the iron ion and Trp398, with an indole-to-metal distance of 5.5 Ĺ. Interestingly, NikA has the natural function to bind to Ni(II) ions; however, the affinity to [Fe(EDTA)(H2O)] exceeds substantially the affinity to Ni(II) ions, and thus the authors suggest that a similar natural metallophore is involved in periplasmic Ni(II) transport by NikA.

A promising strategy for the recognition of proteins by metal complexes makes use of a combination of recognition through the ligand sphere with direct coordination to the target site. Only two examples will be discussed here. Reboud-Ravaux and coworkers developed copper complexes as substrate competitive inhibitors for HIV-1 protease. For example, [bis-(2-pyridylcarbonyl)-amido] copper(II) nitrate dihydrate (Figure 2g) binds with an inhibition constant of 480 μM. Molecular modeling suggests that the catalytic water between Asp25 and Asp125 of HIV-1 protease is directly coordinated to the Cu(II) ion. A current drawback of this class of compounds is the hydrolytical instability of the Cu(II) complexes. One could potentially overcome this problem by designing suitable multidentate ligands or by choosing more kinetically inert metal ions.

       Sadler and coworkers investigated the binding of metal complexes of 1,4,8,11-tetraazacyclotetradecane (cyclam) macrocycles to the CXCR4 coreceptor and lysozyme as a model protein (Figure 2h). In such metallocyclam complexes, the metal is supposed to function by controlling the conformation and configuration of the macrocycle. Additional direct coordinative bonds with the target protein can be formed with the vacant axial coordination sites. One of the most potent members of this family is the bicyclam AMD3100 (Figure 2), which is in clinical trials for the treatment of AIDS. The anti-HIV activity correlates with its binding to the coreceptor protein CXCR4. Interestingly, the complexation of Zn(II) enhances the binding strength to CXCR4 and also its anti-HIV activity.


       Metal compounds provide new opportunities for building structures with unique and defined three-dimensional globular shapes in an economical fashion, and thus complement molecular diversity created by purely organic scaffolds. This access to unexplored chemical space could lead to the discovery of molecules with unprecedented properties. A key aspect for using metal-containing compounds as structural scaffolds is the kinetic stability of the coordination sphere in the biological environment. This can be accomplished with multidentate ligands or, more generally, by employing kinetically inert metals such as ruthenium. Future work will increasingly rely on combinatorial chemistry of metal complex libraries followed by screening against selected targets or even phenotypic assays. Furthermore, it is also appealing to complement the structural role of metals with their special physicochemical, reactive, and/or catalytic properties in one molecule to yield compounds with new abilities to probe and modulate biological processes.

(Based on the article written by Eric Meggers and published in Current Opinion in Chemical Biology, (2007), Vol1, p.287-292)








Current Applications and Future Potential for Bioinorganic Chemistry in the Development of Anticancer Drugs



       Metals – in particular, transition metals – offer potential advantages over the more common organic-based drugs, including a wide range of coordination numbers and geometries, accessible redox states, ‘tune-ability’ of the thermodynamics and kinetics of ligand substitution, and a wide structural diversity. Medicinal inorganic chemistry is a thriving area of research , which was initially fueled by the discovery of the metallopharmaceutical cisplatin about 40 years ago. Today, more than 30 years after its approval as a chemotherapeutic agent, cisplatin is still one of the world's best-selling anticancer drugs. It is mainly used in the treatment of ovarian, head and neck, bladder, cervical and lymphomas cancers. Over the past decades, several cisplatin analogs have been screened as potential antitumor agents, but of these, only two (carboplatin and oxaliplatin) have entered worldwide clinical use .

       Regardless of the achievements of current platinum drugs, there are some major drawbacks: they are efficient only for a limited range of cancers; some tumors can have acquired or intrinsic resistance; and they often cause severe side-effects, such as nausea, bone marrow suppression and kidney toxicity. Although approximately ten other platinum compounds are currently in clinical trials, the cisplatin derivatives have not been able to address sufficiently many of the disadvantages associated with cisplatin. There is a need, therefore, for new approaches that are purposefully designed to circumvent these drawbacks. The field of metal-based anticancer drug design can be divided into two different approaches: classical and nonclassical chemotherapeutics.

       Cisplatin's mode of action involves distortion to DNA. Here, we use the term ‘classical chemotherapeutics’ to refer to drugs that target DNA. Classical drugs based on other metals can address the problems associated with platinum drugs and are attracting increasing interest. At present, several metal-based compounds are known to have promising antiproliferative effects in a wide range of tumors with novel modes of DNA binding; this will be discussed in the section ‘Classical nonplatinum metal compounds’.

       Recent progress in the field of cell biology has resulted in the discovery of receptors and growth factors that are upregulated in cancer cells. These provide new targets for anticancer drug design. Examples of nonclassical chemotherapeutics with proteins and enzymes as targets are emerging; this will be discussed in the section ‘Nonclassical metal compounds’.

       In addition, there is continuing interest in designing drugs that can be activated selectively in the tumor by cellular processes or controlled external activation. Extensive studies on the behavior of metal complexes under biologically relevant conditions have revealed some promising approaches for targeted anticancer drug design with classical and nonclassical targets (‘Prodrug strategies’).

Classical Nonplatinum Metal Compounds

       Nuclear DNA is considered to be the ultimate target of cisplatin and related platinum therapeutics. Before DNA attack, cisplatin undergoes aquation. Although the activated (aquated) cisplatin can interact with other biomolecules, its antitumor activity derives from its capability to form bifunctional DNA crosslinks, which causes the DNA to distort (kink,). The platinum-induced kink in the DNA is considered to be the crucial lesion that leads to a chain of events that includes protein recognition (e.g. by HMG) and eventual apoptosis.

       In this section, some examples of other metal-based therapeutics that target DNA are given. Their exploration might result in drugs that produce distinctly different lesions on DNA and overcome acquired or inherent cisplatin resistance or might prove to be more active toward tumors that are nonresponsive to current chemotherapy.


       Ruthenium compounds containing RuII or RuIII are considered to be suitable candidates for anticancer drug design because they exhibit a similar spectrum of kinetics for their ligand substitution reactions as platinum(II). Several ruthenium compounds display promising anticancer activity, and two ruthenium(III) complexes have entered clinical trials: trans-[RuCl4(DMSO)(Im)]ImH (NAMI-A, where Im = imidazole, ) and trans-[RuCl4(Ind)2]IndH (KP1019, where Ind = indazole, ). NAMI-A is more active against metastases than against primary tumors. By contrast, the structurally similar KP1019 is active against primary tumors. It is believed that the activity of the ruthenium(III) compounds is dependent on the in vivo reduction to the more reactive ruthenium(II) species . This has led to increased interest in the anticancer potential of ruthenium(II) compounds. Much work has focused on the anticancer potential of half-sandwich Ru(II) arene complexes of the type, [(η6-arene)Ru(YZ)(X)], where YZ is a bidentate chelating ligand and X is a good leaving group (e.g. Cl,). These half-sandwich ‘piano-stool’ complexes offer much scope for design, with the potential to vary in each of the building blocks (arene, chelated ligand YZ and monodentate ligand X) to enable modifications of thermodynamic and kinetic parameters.

       Some of the half-sandwich Ru(II) arene complexes display promising in vitro and in vivo anticancer activity). These monofunctional compounds bind coordinatively to N7 of guanine in DNA, which can be complemented by intercalative binding of an extended arene, as well as specific hydrogen-bonding interactions between the chelating ligand and C6O of guanine. These additional interactions result in unique modes of binding to duplex DNA and structural distortions that are distinctly different from those caused by cisplatin ). This might explain why these compounds are not crossresistant with cisplatin. Indeed, it has been found that increasing the size of the coordinated arene increases their activity in the human ovarian cancer cell line . Changing the chelating ligand in these ruthenium arene complexes also seems to have an enormous effect on their kinetics and even changes their nucleobase selectivity . It is believed that in vivo, the aquation of the chloro complex is largely suppressed in intracellular fluids where high chloride concentrations are found (100mm), whereas in the cell nucleus, where the chloride concentration is lower (4mm), the complex forms predominately the active aqua species .

       Another interesting class of ruthenium compounds containing arylazopyridine (azpy) ligands shows promising cytotoxic activity that is structurally dependent. Three of the five possible isomers of [Ru(azpy)2Cl2] (α, β and γ, ) have been reported, where the α isomer represents the cis,trans,cis, β the cis,cis,cis and γ thetrans,cis,cis orientation of the chlorides, the pyridine and the azo nitrogens, respectively. The α and γ isomers show higher toxicities than the β isomer . Indeed, DFT calculations suggest that the ability of the isomers to intercalate into DNA decreases from γ > α > β isoforms . Recently, several isomeric forms of multinuclear ruthenium complexes with bridging azpy ligands have been reported ; the γ/γ isomeric form exhibits the highest cytotoxicity, more than 30-fold higher than cisplatin in breast cancer cells.


       The anticancer potential of osmium, the heavier congener of ruthenium, has been explored recently. Osmium complexes have a reputation for being either toxic (OsO4) or substitution-inert (OsIIand OsIII complexes), and as a consequence, their therapeutic potential has been little explored. However, Sadler and coworkers have synthesized some osmium(II) arene complexes with cancer cell cytotoxicity that is comparable to the clinical drugs, carboplatin and cisplatin. This was achieved by systematically varying the nature of the chelating ligand to fine-tune both the kinetics and thermodynamics of reactions of the osmium compounds in aqueous solution . The OsII arenes are believed to interact with DNA in a similar manner to their ruthenium analogs (i.e. binding to N7 of guanine in combination with H-bonding and noncovalent arene-DNA interaction). Interestingly, binding of OsII arenes to calf thymus DNA gives rise to a large unwinding of double-helical DNA, unlike cisplatin, which causes DNA bending . These osmium complexes do not display crossresistance with cisplatin toward cancer cells, suggesting promise for addressing the problem of intrinsic or acquired resistance in chemotherapy.

Nonclassical Metal Compounds

       The traditional platinum-based therapeutics and the organometallic complexes discussed in the previous section owe their anticancer activity to their nonrepairable interaction with DNA and make use of the fast replication and mitotic processes of malignant cells. Drugs that are able to target cellular signaling pathways overexpressed in cancer cells provide attractive approaches for anticancer drug design. Although less studied than the metallodrug–DNA interactions, some examples of metallodrugs that interact with specific proteins and enzymes are given below.


       Gold complexes are well-known pharmaceuticals, mainly for their application as drugs to treat rheumatoid arthritis. Some tetrahedral Au(I) phosphine complexes display a wide spectrum of anticancer activity in vivo, especially in cisplatin-resistant cell lines . Their cytotoxicity is mediated by their ability to inhibit mitochondrial human glutathione reductase (hGR) and thioredoxin reductase (hTrxR) irreversibly . In particular, phosphol-containing gold(I) complexes are highly potent nanomolar inhibitors of both hGR and hTrxR . hTrxR is associated with many cellular processes, such as antioxidant defence and redox homeostasis, and is found at elevated levels in human tumor cell lines.

       Gold (III) is isoelectronic and isostructural with Pt(II); therefore, gold(III) analogs of Pt(II) drugs were investigated for their biological potential soon after the appearance of cisplatin in the clinic. Unfortunately, they were found to be relatively unstable and easily reduced to metallic gold under physiological conditions . In recent years, however, several gold (III) compounds that incorporate ligands to increase the stability to the gold(III) center have been reported. For example, gold(III) porphyrins exhibit in vitro and in vivo activity in hepatocellular and nasopharyngeal carcinoma . Other gold(III) compounds with promising biological activity include gold(III) bipyridyl compounds, dinuclear gold(III) oxo complexes  and gold(III) dithiocarbamates . For these compounds, the mitochondria and the proteasome are thought to be targets .


       The chemical behavior of gallium(III) is similar to that of ferric iron (FeIII) but differs in that GaIII is nonreducible under physiological conditions, whereas FeIII is readily reduced to FeII. This difference provides therapeutic potential for gallium(III). Currently, two compounds – gallium tris-8-quinolinolate (KP46) and gallium tris-maltolate– are being investigated in clinical trials . Their mechanism of action is associated with the inhibition of ribonucleotide reductase (RR). The enzyme RR catalyzes the conversion of ribonucleotides to deoxyribonucleotides and is produced during the transition from the G1 to the S phase of the cell cycle as a prerequisite for DNA replication; it is highly expressed in tumor cells.


       Interestingly, Meggers et al.have developed kinetically inert organometallic complexes that act as scaffolds to mimic the organic enzyme inhibitor staurosporine, a potent inhibitor of various kinases. In these metal-based inhibitors, the carbohydrate unit of staurosporine is replaced with ruthenium fragments . Structural variation by substitution of the ligands on the metal results in picomolar protein kinase inhibitors. They are highly toxic toward human melanoma cells. The ruthenium staurosporine bioconjugate was recently investigated as an inhibitor for glycogen synthase kinase, a major regulator of p53 localization and expression. The ruthenium staurosporine complex acts as a potent p53 activator and induces apoptosis in otherwise chemoresistant melanoma cells .

       A family of organometallic RuII compounds containing monodentate phosphaadamantane (pta) ligands exhibits moderate in vitro activity, and some compounds show no activity in healthy cells up to millimolar concentrations. The pta compounds show little activity against primary tumors in vivo, although they exhibit some capacity to reduce lung metastases derived from a mammary carcinoma xenograft grown in mice . The cytotoxicity of the RuII pta compound, [Ru(η6-p-cymene)Cl2(pta)], in EAC cells is thought to be mediated by mitochondrial and Jun-N (amino)-terminal kinase (JNK)–p53 pathways .


       Some hexacarbonyl dicobalt complexes exhibit promising activity against several human cancer cell lines . In particular, a cobalt–alkyne analog of the anti-inflammatory drug aspirin is potently active in breast cancer cell lines. Its toxicity has been attributed to its ability to inhibit cyclooxygenase-1 and -2 . This seems to be a promising approach because the inhibition of cyclooxygenase delays tumor growth and improves response to conventional cancer therapies.

       Another hexacarbonyl dicobalt series of compounds containing nucleoside ligands  displays antiproliferative activities with IC50 values in the range of 5–50 μm in human breast cancer cell lines .

       The family of cysteine cathepsin proteases has been validated recently as an important enzymatic class to target in cancer. More specifically, cathepsin B and L have been involved in multiple stages of tumor development. Metal-based compounds reported to show promising inhibition of cathepsin B include linear gold(I) complexes containing thiolate and phosphine ligands , dinuclear palladium complexes (biphosphinic palladacycle complexes)  and several oxorhenium(V) complexes 

       Other metal-based drugs in preclinical or early phase of clinical development not mentioned in the previous two sections contain vanadium, rhodium, copper, bismuth and lanthanide metals .

Prodrug Strategies

       Delivery of metal-based drugs to their targets poses one of the biggest challenges in cancer chemotherapy. A drug needs to be sufficiently reactive to bind to the biological target but not so reactive that it will be deactivated by the many biomolecules encountered on the way. One strategy involves the design of prodrugs. Prodrugs are drug derivatives that can undergo a transformation in vivo to release the active species, with improved physiochemical, biopharmaceutical and pharmacokinetic properties. For metal-based therapeutics, this prodrug activation might be realized by a photochemical process , by oxidation or reduction of the metal or a ligand, or by ligand substitution. This requires extensive knowledge of ligand substitution rates, redox potentials, photochemistry and choice of metal and, in addition, the effect of the other coordinated ligands in the complex.

       In recent years, there has been a focus on making prodrugs selective. To achieve this, the prodrug has to be activated by specific physiological characteristics of tumors, such as the reducing environment of the cell, pH or cancer cell permeability. Some examples of different prodrug strategies, including tumor selectivity and drug delivery strategies, will be discussed in the following paragraphs.

Photoactivation as a Prodrug Strategy

       The activation of a metal-based prodrug can be realized by photochemical means. The advantage of using light as an external stimulus is that it enables local treatment of the tumor, minimizing side-effects. The poor penetration of tissue by short-wavelength light, however, is a serious limitation: longer wavelength light (red) penetrates more deeply than UVA light. For a photochemical treatment to be effective in the clinic, the wavelength of activation should be within the range 350–900 nm; shorter wavelengths cause damage to tissue, and higher wavelengths usually carry insufficient energy to activate the prodrug. Currently used in the clinic, photodynamic therapy (PDT) treats readily accessible tumors (i.e. skin, neck and bladder) by the administration of a nontoxic photosensitizer and subsequent irradiation of the tumor site . Upon irradiation, the photosensitizer, typically a porphyrin, becomes excited and this energy is transferred to ground-state triplet oxygen (3O2) to form highly reactive singlet oxygen (1O2), leading to cell death. Metal-bound porphyrins can have marked effects on the tumor-localizing properties of the photosensitizer. Indeed, metal-containing photosensitizers for cancer treatment are currently well represented in clinical trials and include a lutetium porphyrin derivative (Lutetium texaphyrin) , CGP55847 (Zn), Photosense (Al) and Purlytin (Sn) . All these photosensitizers need oxygen to generate their cytotoxic effects; however, cancer cells are often deficient in oxygen.


       Recently, several Rh and Ru complexes that exhibit oxygen-independent light-induced anticancer activity, have been reported. For example, Barton et al. have shown that several octahedral RhIIIcomplexes with extended diimine ligands bind only weakly to DNA in the absence of light but on photoactivation bind to DNA and cleave the DNA backbone with high specificity for mismatched DNA . Recently, the effects of variation of the ancillary ligand on the ability of these compounds to target DNA mismatches in vitro and in vivo have been explored .


       The general kinetic inertness of PtIV complexes compared to PtIIcomplexes has been widely exploited in the design of potential prodrugs. The PtIV compound satraplatin, [Pt(cha)Cl2(OAc)2(NH3)] (where cha is cyclohexylamine; , has been abandoned recently in phase III clinical trials for the treatment of hormone-refractory prostate cancer . Substitution reactions of PtIVcomplexes under physiological conditions are very slow or do not take place at all. Therefore, intracellular reduction to PtII is thought to be essential for cytotoxic activity. This reduction might be achieved by cellular reducing agents (discussed in the next section) or by irradiation with light, enabling site-specific activation of the drugs trans-Dihydroxido platinum(IV) prodrugs containing two azido ligands in trans or cis positions relative to each other are nontoxic in the dark but show cytotoxicity toward various human cancer cell lines upon irradiation . In particular, a PtIV diazido complex containing pyridine trans to ammonia, trans,trans,trans-[Pt(N3)2(OH)2(py)(NH3)], is up to 80 times more cytotoxic than cisplatin in ovarian cancer cells upon irradiation but inactive and stable toward biological reductants in the dark. One photoactivation pathway for these complexes (among several possibilities) involves ligand-to-metal charge transfer from the azido ligands to PtIV, resulting in reduction to the reactive PtIIspecies. The produces azidyl (N3radical dot) radicals that rapidly combine and decompose to produce nitrogen gas. Aquation of the PtIIcompound and subsequent binding to DNA (and possibly proteins) leads to its cytotoxic effect. Notably, the mechanism of DNA platination by the trans-azide complex is different from cisplatin, and cell death is not solely dependent on activation of the caspase 3 pathway . It is apparent that photoactivation can produce excited states with unusual reactivity and provide routes to intervening in biological pathways not available to ground-state drugs.

Redox Activation as a Prodrug Strategy

       The redox behavior of metal complexes offers chemical reactivity that is not accessible to purely organic molecules and, therefore, can yield novel metallodrugs with new mechanisms of drug action. For the prodrug to be successful, the metal complex should possess biologically accessible redox potentials. Tuning their properties to the reducing environments of tumor cells might lead to novel targeted strategies.


       Well-established examples are ferrocene derivatives of the breast cancer drug tamoxifen . They display potent activity against both estrogen-dependent and estrogen-independent breast cancer cells, whereas tamoxifen alone is active only against estrogen-dependent cells. The activity of the ferrocene tamoxifen derivatives (ferrocifens) in estrogen-independent cells is attributed to the redox properties of the FeIIcomplex, leading to oxidative damage to DNA. The mechanism of action of ferrocifens in estrogen-dependent cells is likely to be similar to that of tamoxifen itself. It is noteworthy that one of the most active ferrocene derivatives exhibits less toxicity than tamoxifen itself. A recent study on ferrocene tamoxifen derivatives with modified side chains has established the minimal structural requirements to obtain cytotoxicity .


       A prodrug approach for the inhibition of enzymes by cobalt complexes has been explored by Hambley et al. . Their strategy involves the complexation of the matrix metalloproteinase (MMP) inhibitor marimastat to a CoIII complex to achieve selective delivery of MMP to the tumor The resulting CoIII complex provides an inert carrier system for the transportation of the inhibitor. The prodrug is activated by a bioreduction pathway producing a labile CoII complex, which results in the release of the MMP inhibitor. The hypoxic nature of the tumor should prevent oxidation back to the cobalt(III) complex, thus achieving selective release in tumor cells. Indeed, increased cytotoxicity was observed for the cobalt prodrug in in vivo tumors in mice compared to the MMP inhibitor alone. Unfortunately, both the inhibitor and the prodrug promote metastasis.


       Half-sandwich ruthenium arene complexes containing iodo and phenylazopyridine ligands exhibit remarkable inertness toward ligand substitution in aqueous solution but are highly toxic in human ovarian and lung cancer cells. Whereas azopyridine ligands alone are difficult to reduce, these azopyridine RuIIcomplexes have reduction potentials that are biologically accessible. The toxicity of these complexes can be attributed to their ability to induce redox reactions inside the cell leading to reactive oxygen species. Interestingly, the redox cycle involves the oxidation of the strong reducing agent glutathione present in millimolar concentrations, in the presence of micromolar concentrations of the ruthenium complex .

       Organometallic ruthenium arene complexes containing thiolato ligands can be activated by oxidation  Under physiologically relevant conditions, the monodentate thiolato ruthenium complex is capable of efficient acceptance of an oxygen atom from an intermediate in glutathione (GSH) oxidation. This shows that GSH can act as a source of reactive oxygen species, able to induce oxidation of organometallic complexes that are themselves stable in air  Ruthenium sulfenate adducts seem to be more labile than the parent thiolato complexes (e.g. toward DNA binding), perhaps through protonation of the sulfenato oxygen atom.


       The relative kinetic inertness of six-coordinate octahedral PtIVcomplexes can be used as a prodrug approach to overcome some of the problems associated with (four-coordinate, square-planar) cisplatin. For this, intracellular reduction to PtII is essential for activation and cytotoxic activity. The two extra ligands in the axial positions enable the inclusion of different kinds of bioactive ligands, which might lead to platinum anticancer complexes with improved efficacy.

       In one such approach, an attempt to target specifically estrogen-positive malignancies (such as breast and ovarian cancers) led to the design of several estrogen-tethered platinum(IV) complexes. This is a cancer drug target because estrogen-receptor-positive breast cancer cells treated with estrogen are more sensitive to cisplatin. Upon intracellular reduction, the complex releases cisplatin and two molecules of estrogen derivative. The latter induces upregulation of the high-mobility group domain protein HMGB1 in a human breast cancer cell line. The HMGB1 protein shields platinated DNA from nucleotide-excision repair.

       In an attempt to overcome cisplatin resistance, a similar approach has been used to inhibit glutathione-S-transferase (GST), the main cellular defence against xenobiotics. For this, Dyson et al. attached the GST inhibitor ethacrynic acid to a PtIV complex (ethacraplatin,).

       In recent years, effort has also been given to the design of novel drug delivery systems that are capable of increasing the cellular uptake, as well as directed delivery, of metallodrugs only to tumor cells. Interesting approaches include attachment of a platinum drug to a pH-sensitive polymer , attachment of a PtIV prodrug noncovalently to single-walled carbon nanotubes , encapsulation of platinum drugs in lipid-based nanocapsules and attachment of the SV4-40T antigen nuclear localization signal to metallocenes .

Concluding Remarks

       Metal coordination complexes offer a versatile platform for the design of novel anticancer agents. Their properties can be distinct from those of purely organic compounds. Particularly attractive for study are the first-, second- and third-row transition metals, which have variable oxidation states, coordination numbers and the ability to bind to a wide variety of types of ligands (e.g. halides, O, S, N, P and C). In particular, metals in the second and third rows often exchange their ligands slowly, on minutes-to-hours timescales that enable at least some of the original ligands to remain bound to the metal en route to the target site. In general (with some exceptions), because they can undergo ligand exchanges, metal complexes are prodrugs; ligand substitution can activate the metal complex toward binding to target molecules. A key element in the design process is the control of both the thermodynamics (state of equilibrium) and kinetics of ligand substitution events that can occur in vivo; for example, the aquation of metal–chloride bonds as the chloride concentration diminishes from extracellular to intracellular (cytoplasmic and nuclear) compartments.

       In addition, both metal-centered and ligand-centered redox processes are of interest. The former can trigger activation by ligand release (e.g. reduction of substitution-inert CoIII to labile CoII), and the latter can trigger the initiation of the production of reactive oxygen species (e.g. azopyridine RuII arenes), as part of the cytotoxic mechanism. The possibility of using light to activate metal complexes selectively in tumor cells is also an intriguing one. Reactions of excited-state metal complexes can be distinctly different from those of ground-state complexes, giving rise to the possibility of interfering in biochemical pathways with highly reactive novel species.

       Cisplatin and the successive generations of platinum-based anticancer drugs (carboplatin and oxaliplatin) have demonstrated that metal coordination complexes can play an important part in anticancer treatment regimes in the clinic. The exploration of other transition metal complexes, as well as targeting and activation strategies, should lead to future generations of drugs that can overcome some of the disadvantages associated with cisplatin therapy, including the reduction of side-effects, widening the spectrum of activity, and resistance.

       Finally, it is worth emphasizing the subtlety with which ligands control the reactivity of transition metal ions and, also, the reciprocal effects that metal ions can have on the properties of ligands. Both the metal and the ligands can have important roles in the recognition of target sites. The subtle effects exerted by ligands can be both steric and electronic in nature. Modern theoretical methods (e.g. Amsterdam Density Functional Theory) and techniques (e.g. high-resolution electrospray mass spectrometry and multinuclear polarization transfer NMR spectroscopy) are likely to aid our understanding of the chemical and biochemical reactivity of metal complexes and the construction of meaningful structure–activity relationships. For this purpose, studies of the chemistry of metal complexes under physiologically relevant conditions (e.g. biological screening conditions) become very important.

(Based on the article written by Sabine H van Rujt & Peter J Sadler  and published in Drug Discovery Today, Vol. 14 No. 23/24, Dec., 2009)






Organometallic compounds as new drugs? Cobalt-containing aspirin complex with potential anti-tumor properties

       Most drugs used today are purely organic compounds. Stimulated by the enormous success of the inorganic complex cisplatin in tumor treatment, interest in metal complexes has grown. Within cells, metal complexes can participate in reactions that are not possible with conventional organic substances.

       Aspirin (acetylsalicylic acid) belongs to the family of nonsteroidal antirheumatics (NSAR), which have anti-inflammatory and pain-relieving effects. The pharmacological effects of NSARs stem from the inhibition of enzymes in the cyclooxygenase family (COX). These enzymes not only play a central role in inflammatory processes, they also seem to be involved in tumor growth. NSARs have thus come into focus as potential cytostatics. It may be possible to improve anti-tumor activity in the case of aspirin by binding it to an organometallic fragment.

       Within the scope of the “Biological Function of Organometallic Compounds” research group funded by the Deutsche Forschungsgemeinshaft (German Research Foundation, DFG), the team determined that “Co-Aspirin”, a hexacarbonyldicoboalt-aspirin complex, inhibits COX activity differently to aspirin. Whereas the effect of aspirin stems from the acetylation of a serine residue in the active center of COX, Co-Asprin does not attack this side chain, instead acetylating several other sites. This may block access to the active center of the enzyme, resulting in a different activity spectrum for the drug.

       Experiments with zebra fish embryos showed that in contrast to aspirin, Co-Aspirin inhibits both cell growth and the formation of small blood vessels (angiogenesis). Tumors are dependent on newly formed blood vessels for their nutrients and can be starved out by the inhibition of angiogenesis. In addition, Co-Aspirin modulates other tumor-relevant metabolic pathways. For example, it activates the enzyme caspase, which is involved in processes that lead to apoptosis (programmed cell death).

(PHYSOROG.com, Jan., 13, 2009)

Metal complexes in the management of parasitic diseases: In vitro antiprotozoal studies of metal complexes of some antimalarial drugs

       Parasitic infections are common in developing areas of the world, and affect an estimated 3.5 billion people. The three infections which constitute the highest disease burden are malaria caused by Plasmodium spp., African human trypanosomiasis caused by Trypanosoma brucei rhodesiense and T. b. gambiense, and Chagas disease caused by Trypanosoma cruzi. Malaria was successfully reduced after World War II because of easy access to cheap insecticide and readily available drugs. At present, there are an estimated 300–500 million cases, and up to 2.7 million deaths each year. The genus Trypanosoma contains a large number of parasitic species which infect wild and domesticated animals and humans. Only four drugs are in use for the treatment of trypanosomiasis. All of them have to be administered parenterally and frequently cause serious side effects. The emergence and spreading of parasites resistant to drugs in use for their treatment indicates that novel compounds need to be developed by identification of novel chemotherapeutic targets. Hence, the search for new anti-malarial therapies is a high priority for control of the disease. In the search for novel drugs against resistant parasites, the use of metal complexes has received considerable attention in recent years. In our effort to contribute to the search for novel chemotherapeutic drugs against parasitic diseases, we present the antiplasmodial and antitrypanosomal screening of metal complexes of some antimalarial drugs.

       The metal complexes were synthesized as reported in the literature. The tests were performed as micro plate assays using T. b. rhodesiense (STIB 900), T. cruzi (Tulahuenc C4), Leishmania donovani (MHOM-ET-67/L82) and K1 strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine). The following were used as standard: melarsoprols (T. b. rhodesiense), Benznidazole (T. cruzi), Miltefosine (L. donovani) and chloroquine (P. falciparum).. The Cu(II) complex of trimethoprim [Cu- (TMP)2(CH3COO)4] exhibited the highest antiplasmodial activity (IC50 = 3.7231 µM). It is more active than trimethoprim (IC50 = 4.733 µM) and less toxic than trimethoprim (IC50 = 46.474 µM), and the widely used chloroquine (IC50 =188.5 µM)13. All the metal complexes showed some level of activity against T. b. rhodesiense, with two Cu(II) complexes being the most active. The Cu(II) complexes of trimethoprim [Cu(TMP)2- (CH3COO)4] showed the highest activity (IC50 = 3.411 µM), while the Cu(II) complex of sulphadiazine [Cu(SD)2(H2O)2], (IC50 = 15.063 µM) was the least toxic of all the complexes. The Cu(II) complex of trimethoprim (IC50 = 16.3 µM) was the only active compound against T. cruzi, while the Pt(II) (IC50 = 11.9 µM) and Pd(II) (IC50 = 16.6 µM) complexes of trimethoprim were the only active compounds against axenic L. donovani. The incorporation of metals into the drugs has improved the antiprotozoal activities of some of the metal complexes. The Cu(II) complex of trimethoprim showed enhanced antiplasmodial activity against the resistant strain of P. falciparum, while both Cu(II) complexes of sulfadiazine and trimethoprim showed activity against T. b. rhodesiense, and were far less toxic than chloroquine. Although the activities of the complexes are not yet a challenge for the current generation of drugs in use, they will serve as leads for further structural modifications in the search for alternative therapy.

(Current Science Vol. 95 No.12 (Dec., 25, 2008)

Ruthenium-based chemotherapeutics: are they ready for prime time?

       Since the discovery of cis-platinum, many transition metal complexes have been synthesized and assayed for antineoplastic activity. In recent years, ruthenium-based molecules have emerged as promising antitumor and antimetastatic agents with potential uses in platinum-resistant tumors or as alternatives to platinum. Ruthenium compounds theoretically possess unique biochemical features allowing them to accumulate preferentially in neoplastic tissues and to convert to their active state only after entering tumor cells. Intriguingly, some ruthenium agents show significant activity against cancer metastases but have minimal effects on primary tumors. Two ruthenium-based drugs, NAMI-A and KP1019, have reached human clinical testing. This review will highlight the chemical properties, mechanism of action, preclinical data, and early phase clinical results of these two lead ruthenium compounds. Other promising ruthenium agents will also be reviewed with emphasis on the novel ruthenium compound ONCO4417, and DW1/2 that has demonstrated Pim-1 kinase inhibition in preclinical systems. Further development of these and other ruthenium agents may rely on novel approaches including rational combination strategies as well as identification of potential pharmacodynamic biomarkers of drug activity aiding early phase clinical studies.

(Cancer Chemother Pharmacol 2010 Mar 6.and PMID; 20213076)

Antiproliferative effect and genotoxicity of novel synthesized palladium complexes with organoarsenic ligands

       Three new palladium complexes with general formula [PdCl2L2], where L = heterofunctional organoarsenic ligand: (2-isopropoxyphenyl)diphenylarsine (1), (2-methoxyphenyl)-diphenylarsine (2) and (2-hydroxyphenyl)diphenylarsine (3) have been synthesized and fully characterized, including X-ray crystallographic data. Their potential antitumor effect and genotoxicity have been studied as well. The viability test performed on human tumor (MLS) and normal (Hfl-1) cell lines indicates significant cytotoxicity of complexes, which is higher in tumor cells than in normal cells. The lethal doses are comparable with those of standard metal-based chemotherapeutical drugs (carboplatin and oxaliplatin). These palladium complexes exhibit a higher cytotoxicity against tumor cells as against normal cells in vitro. A new static cytometric method was developed and simultaneously the classic AnnexinV test was performed. Complex 2has an important capacity to induce apoptosis in tumor cells. The apoptotic process is triggered due to the interaction of these complexes with secondary structure of DNA in treated cells. The alkaline single-cell gel assay shows that the level of DNA damages induced by compounds 2and 3 are significantly higher in tumor cells as in normal cells. These studies shown that complexes 1, 2 and 3 have biologic activity, the effect of complex 2 being superior to its platinum analogues, attributable to its structure.

(Journal of Inorganic Biochemistry Volume 103, Issue 12, December 2009, Pages 1739-1747)

Inhibitory effects of the ruthenium complex KP1019 in models of mammary cancer cell migration and invasion

       The effects of indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, or FFC14A), the second ruthenium compound that entered clinical trials, in an in vitro model of tumour invasion and metastasis show that the antitumour effects of this compound might include also the modulation of cell behaviour although its cytotoxicity appears to be predominant over these effects. The comparison with its imidazole analogue KP418 shows however its superiority, being able to control in vitro cell growth and in some instances also in vivo tumour development. These results suggest that the activity of KP1019 is predominantly due to direct cytotoxic effects for tumour cells, evident also in vivo on primary tumour growth and that the effects on modulation of the biological behaviour of the cancer cell can be present but might have only a partial role.

(Net.Based Drugs (2009), 681270 (PMID 19789639)

A novel vanadyl complex with a polypyridyl DNA intercalator as ligand: A potential anti-protozoa and anti-tumor agent

       In the search for new metal-based drugs for the treatment of tumoral and parasitic diseases a vanadyl complex, [VIVO(SO4)(H2O)2(dppz)]·2H2O, that includes the bidentate polypyridyl DNA intercalator dipyrido[3,2-a:2′,3′-c]phenazine (dppz), was synthesized, characterized by a combination of techniques, and in vitro evaluated on the human acute promyelocytic leukemia cell line HL-60 and against Dm28c strain epimastigotes of the parasite Trypanosoma cruzi, causative agent of Chagas’ disease. EPR spectroscopy suggests a distorted octahedral geometry for the complex with the dppz ligand acting as bidentate, binding through both nitrogen donor atoms in an axial–equatorial mode. An oxo group, two water molecules and a sulphate donor occupy the remainder coordination positions. The complex, as well as the anti-trypanosomal reference drug Nifurtimox, showed IC50 values in the μM range against T. cruzi Dm28c strain. In addition the complex exhibited excellent in vitro anti-tumor activity against leukemia (HL-60 cell line) comparable to that of cisplatin, inducing cell death by apoptosis with IC50 values in the micromolar range. Data from gel electrophoresis and atomic force microscopy indicate that the complex interacts with DNA, suggesting that its mechanism of action may include DNA as a target. EPR and 51V NMR experiments were also carried out with aged aerated solutions of the complex to get insight into the stability of the complex in solution and the species responsible for the in vitroactivities observed.

(Journal of Inorganic Biochemistry Volume 103, Issue 10, October 2009, Pages 1386-1394)

Copper in diseases and treatments, and copper-based anticancer strategies.

       Copper is found in all living organisms and is a crucial trace element in redox chemistry, growth and development. It is important for the function of several enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biological molecules involve oxidation-reduction reactions in which they react directly with molecular oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is associated, respectively, with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at molecular levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, respectively. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic molecules. More recently, mixtures of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compounds in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.

(Med Res Rev. 2009 Jul 22 and PMID: 19626597)

Unusual DNA binding modes for metal anticancer complexes

       DNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes.

Biochimie Volume 91, Issue 10, October 2009, Pages 1198-1211)

Synthesis, oxidant properties, and antitumoral effects of a palladium (II) complex of curcumin on human prostate cancer cells.

       A new ionic Pd(II) complex, [(bipy)Pd(Pcurc)][CF3SO3], 1, with the metal center coordinated to two different chelating ligands, the pure curcumin (Pcurc) and the 4,4′-dinonyl-2,2′-bipyridine (bipy), has been synthesized, fully characterized, and its antitumoral mechanism and oxidant property have been investigated. The Pd(II) complex induces both cell growth inhibition and apoptosis of human prostate cancer cells, (LnCaP, PC3, and DU145) through the production of ROS and JNK phosphorylation associated with GSTp1 down-regulation. ROS production induced by complex 1 treatment activated apoptotis through mitochondrial membrane depolarization in all prostate cancer cells, with up-regulation of Bax and down-regulation of Bcl-2 proteins. In addition, while curcumin determines DNA damage and PARP cleavage, complex 1 does not elicit any activation of PARP enzyme. Taken together, these data validate the significance of curcumin complexation to a metal center and its conjugation to another functionalized bioactive ligand in the apoptosis signal transduction and enhancement of cell death in prostate cancer cell lines and suggest the potential of this design strategy in the improvement of the metal-based drugs cytotoxicity.

(J. Med Chem (2009) Jan., 22, 52(2), 484-91)

Carbohydrate-metal complexes and their potential as anticancer agents

       A review. Platinum complex-based chemotherapy is one of the major treatment options of many malignancies. Although severe side effects occur, and only a limited spectrum of tumors can be cured, Pt compds. are used in every second therapy scheme. Thus, many different drug design strategies have been employed for improving the properties of anticancer drugs including pH or redox activation in the tumor, variation of the metal center and therefore the redox and ligand exchange properties, the application of multinuclear metal complexes, the development of targeted approaches, etc. Application of carbohydrate-metal complexes is an example of a targeted approach exploiting the biochem. and metabolic functions of diverse sugars in living organisms for transport and accumulation. Natural carbohydrates and synthetic derivs. possess a manifold of donors endowing them with the ability to coordinate metal centers and providing some addnl. advantages over other ligands, e.g., biocompatibility, nontoxicity, enantiomeric purity, water soly., and well-explored chem. In recent years, several examples of carbohydrate compds. have been developed for diverse medicinal applications ranging from compds. with antibiotic, antiviral, or fungicidal activity and anticancer compds. Herein, metal complexes with carbohydrate ligands are reviewed and the role of the carbohydrate carriers on the antineoplastic activity of these compds., both in vitro and in vivo, is described.

(Current Medicinal Chemistry, vol. 15, num. 25, 2008, p. 2574-2591 Date: 2008)

Emerging protein targets for anticancer metallodrugs: inhibition of thioredoxin reductase and cathepsin b by antitumor ruthenium(II)-arene compounds

       A series of ruthenium(II)-arene (RAPTA) compds. were evaluated for their ability to inhibit thioredoxin reductase (either cytosolic or mitochondrial) and cathepsin B, two possible targets for anticancer metallodrugs. In general, inhibition of the thioredoxin reductases was lower than that of cathepsin B, although selected compds. were excellent inhibitors of both classes of enzymes in comparison to other metal-based drugs. Some initial structure-activity relationships could be established. On the basis of the obtained data, different mechanisms of binding/inhibition appear to be operative; remarkably the selectivity of the ruthenium compds. toward solid metastatic tumors also correlates to the obsd. trends. Notably, docking studies of the interactions of representative RAPTA compds. with cathepsin B were performed that provided realistic structures for the resulting protein-metallodrug adducts. Good agreement was generally found between the inhibiting potency of the RAPTA compds. and the computed stability of the corresponding cat B/RAPTA adducts.

(Journal of Medicinal Chemistry, Vol. 51, No. 21, P. 6773-6781,  2008)






Proteomic approaches in understanding action mechanisms of metal-based anticancer drugs.

       Medicinal inorganic chemistry has been stimulating largely by the success of the anticancer drug, cisplatin. Various metal complexes are currently used as therapeutic agents (e.g., Pt, Au, and Ru) in the treatment of malignant diseases, including several types of cancers. Understanding the mechanism of action of these metal-based drugs is for the design of more effective drugs. Proteomic approaches combined with other biochemical methods can provide comprehensive understanding of responses that are involved in metal-based anticancer drugs-induced cell death, including insights into cytotoxic effects of metal-based anticancer drugs, correlation of protein alterations to drug targets, and prediction of drug resistance and toxicity. This information, when coupled with clinical data, can provide rational basses for the future design and modification of present used metal-based anticancer drugs.

(Met Based Drugs. 2008; 2008: 716329 and PMID: 18670610)











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       Ni(II), Cu(II), and Zn(II) diethyldithiocarbamate complexes show various activities against the proteasome in breast cancer cells.

       Cvek, Boris et al

       Journal of Medicinal Chemistry,51(20), 6256 (Sept., 25, 2008)

       A series of three complexes with diethyldithiocarbamate ligand and three different metals (Ni, Cu, Zn) were prepared, confirmed by X-ray crystallography, and tested in human breast cancer MDA-MB-231 cells. Zinc and copper complexes, but not nickel complex, were found to be more active against cellular 26S proteasome than against purified 20S proteasome core particle. One of the possible explanations is inhibition of JAMM domain in the 19S proteasome lid.

       Synthesis, molecular structure and evaluation of new organometallic ruthenium anticancer agents.

       Camm KD  et al;.

       Dalton Trans. 2009 Dec 28;(48):10914-25. Epub 2009 Nov 16.

       A number of new ruthenium compounds have been synthesised, isolated and characterized, which exhibit excellent cytotoxicity against a number of different human tumour cell lines including a defined cisplatin resistant cell line and colon cancer cell lines. Addition of hydrophobic groups to the ruthenium molecules has a positive effect on the cytotoxicity values. Evidence is provided that, after incubation of a ruthenium compound with a 46 mer oligonucleotide duplex and subsequent nuclease treatment, ruthenium is bound to a guanine residue.

       An organometallic approach for the synthesis of water-soluble ruthenium and platinum nanoparticles.

       Debouttičre PJ  et al.

       Dalton Trans. 2009 Dec 14;(46):10172-4. Epub 2009 Oct 2.

       An organometallic synthesis of ruthenium and platinum nanoparticles and their transfer into water using 1,3,5-triaza-7-phosphaada-mantane as stabilizer is reported.

       Supramolecular interactions between functional metal complexes and proteins.

       Davies CL  et al..

       Dalton Trans. 2009 Dec 14;(46):10141-54. Epub 2009 Nov 2.

       This perspective illustrates the principles and applications of molecular recognition directed binding of transition metal complexes to proteins. After a brief introduction into non-covalent interactions and the importance of complementarity, the focus of the first part is on biological systems that rely on non-covalent forces for metal complex binding, such as proteins involved in bacterial iron uptake and the oxygen-storage protein myoglobin. The second part of the perspective will illustrate how the replacement of native with non-native  metal-centres can give rise to artificial metalloenzymes with novel catalytic properties. Subsequently, examples of spectroscopic probes that exploit the characteristic photophysical properties of metal-complexes for the non-covalent labelling, visualisation and investigation of proteins will be described. Finally, the use of kinetically inert metal complexes as scaffolds in drug design will be discussed and it will be highlighted how the binding of metal ions or organometallic fragments to existing drugs or drug candidates can improve their activity or even alter their mode of action.

       Apoptotic and chemotherapeutic properties of iron (III)-salophene in an ovarian cancer animal model.

       Lange TS  et al.

       Drug Des Devel Ther. 2009 Sep 21;3:17-26.

       The cytotoxicity of organometallic compounds iron(III)-, cobalt(III)-, manganese(II)-, and copper(II)-salophene (-SP) on platinum-resistant ovarian cancer cell lines was compared. Fe-SP displayed selective cytotoxicity (IC(50) at ~1 muM) against SKOV-3 and OVCAR-3 cell lines while Co-SP caused cytotoxic effects only at higher concentrations (IC(50) at 60 muM) and Cu-SP effects were negligible. High cytotoxicity of Mn-SP (30-60 muM) appeared to be nonspecific because the Mn-chloride salt reduced cell viability similarly. The effect of Fe-SP at 1 muM proved to be ovarian cancer cell selective when compared to a panel of cell lines derived from different tumors. The first irreversible step in the induction of cell death by Fe-SP occurred after 3 hrs as indicated by the mitochondrial transmembrane potential (DeltaPsim) and was mainly linked to apoptotic, not necrotic events. To evaluate the toxicity of Fe-SP in vivo we conducted an acute toxicity study in rats. The LD(50) of Fe-SP is >2000 mg/kg orally and >5.5 mg/kg body weight by intraperitoneal injection. An ovarian cancer animal model showed that the chemotherapeutic relevant dose of Fe-SP in rats is 0.5-1 mg/kg body weight. The present report suggests that Fe-SP is a potential therapeutic drug to treat ovarian cancer.

       In vivo tumour and metastasis reduction and in vitro effects on invasion assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model.

       Bergamo A  et al.

       J Inorg Biochem. 2010 Jan;104(1):79-86. Epub 2009 Oct 14.

       Authors have compared the organometallic arene complexes [(eta(6)-biphenyl)M(ethylenediamine)Cl](+) RM175 (M=Ru(II)) and its isostructural osmium(II) analogue AFAP51 (M=Os(II)) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion  after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6x more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231  cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic  activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo.

       Identifying potent, selective protein tyrosine phosphatase inhibitors from a library of Au(I) complexes.

       Karver MR  et al.

       J Med Chem. 2009 Nov 12;52(21):6912-8.

       Therapeutic inhibition of protein tyrosine phosphatase activity is a compelling yet challenging approach to the treatment of human disease. Toward this end, a library of 40 gold complexes with the general formula R(3)P-Au-Cl was screened to identify novel inhibitors of PTP activity. The most promising inhibitor obtained  for the lymphoid tyrosine phosphatase LYP, (2-pyridine)(Ph(2))P-Au-Cl, is one of  the most potent and selective LYP inhibitors identified to date with an IC(50) of 1.5  0.3 microM, 10-fold selectivity for LYP over PTP-PEST, HePTP, and CD45 in vitro, and activity in cellular studies as well.

       Comparative biological evaluation of two ethylene linked mixed binuclear ferrocene/ruthenium organometallic species.

       Ott I  et al.

       Bioorg Med Chem Lett. 2010 Feb 1;20(3):866-869. Epub 2009 Dec 28.

       Two ethylene linked binuclear mixed ferrocene/ruthenium complexes were biologically investigated in comparison to structurally related mononuclear ferrocene or ruthenium species with styryl substituents or ligands. Results indicated that the electron distribution (but not the redox potential), cellular  uptake and (to some minor extent) anti-estrogenic effects were the key contributors to antiproliferative effects observed in tumor cell lines.

       Organometallic complexes that interconvert between trimeric and monomeric structures as a function of pH and their effect on human cancer and fibroblast cells

       Ang, Wee Han et al.

       Journal of Organometallic Chemistry, 694(6), 968 (Mar., 15, 2009)

       Organometallic half-sandwich complexes based on ruthenium with aminomethyl-substituted 3-hydroxy-2-pyridone ligands exist in aqueous solution as monomeric O,O'-chelate complexes or trimeric metallomacrocycles depending upon the pH. Authors hypothesized that administration of the compounds as stable trimers, which subsequently convert to active monomers at the reduced pH of the cancer environment, could facilitate their delivery to cancer cells without undergoing deactivation. Thus, the compounds were evaluated against cancer and fibroblast cell lines in vitro. A series of rhodium complexes, which exist mainly as monomers at neutral pH, were also studied for comparative purposes.

       Tuning the anticancer activity of maltol-derived ruthenium complexes by derivatization of the 3-hydroxy-4-pyrone moiety

       Kandioller, Wolfgang et al.

       Journal of Organometallic Chemistry, 694(6), 922 (Mar., 15, 2009

       Organometallic ruthenium(II)-arene complexes coordinated to maltol-derived ligands were prepared and their anticancer activity against human tumor cell lines was studied. In addition, their hydrolysis behavior and reaction with 5'-GMP was tested and compared to the parent compound chlorido[2-methyl-3-(oxo-[kappa]O)-pyran-4(1H)-onato-[kappa]O4]([eta]6-p-cymene)ruthenium(II) (Ru-maltol). Improved stability and in vitro anticancer activity at maintained GMP binding capability were observed, in comparison to the Ru-maltol complex.

       New trends for metal complexes with anticancer activity

       Bruijnincx, Pieter CA et al.

       Current Opinion in Chemical Biology, 12(2), 197 (Apr., 2008)

       Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side-effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selective delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in [`]metals in medicine'.

       Studies on the reactivity of organometallic Ru-,Rh- and Os-pta complexes with DNA model compounds

       Dorcier, Antoine et al.

       Journal of Inorganic Biochemistry, 102 (5-6) 1066 (May 2008)

       The reactions of arene-metal complexes (arene = p-cymene, benzene or pentamethylcyclopentadienyl, metal = Ru, Rh or Os), including 1,3,5-triaza-7-phosphatricyclo-[]decanephosphine (pta) and chloro co-ligands, with 9-methylguanine, adenine, and a series of nucleosides were studied in water to ascertain the binding modes. The products were characterized by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Tandem mass spectrometry was found to provide excellent information on preferential binding sites. In general, the N7 position on guanine (the most basic site) was found to be the preferred donor atom for coordination to the metal complexes. The X-ray structures of the precursor complexes, [([eta]5-C10H15)RhCl(pta-Me)2]Cl2, [([eta]6-C10H14)OsCl(pta)2]Cl, and [([eta]6-C6H6)OsCl2(CH3CN)], are also reported.

       Transition metal carbonyl clusters with ene-yne ligands

       Gervasio, Giuliana et al.

       Inorganica Chimica Acta, 350, 215 (July 4, 2003)

       Ene-yne molecules are found as natural products. Natural and synthetic ene-ynes are actively studied and partly used as anticancer drugs. Conjugated and non-conjugated ene-yne molecules are widely used as synthons in organic reactions promoted by organometallic compounds. Surprisingly, the coordination of ene-ynes to transition metal clusters has not been fully rationalized up to now; the same happens for the (not very many) examples of their reactivity and of their potentials uses. In this paper the synthetic routes leading to (and the structures of) transition metal clusters containing ene-yne ligands are described. Comparisons with the chemistry of di-ynes coordinated to transition metal clusters are made.

       Titanium(IV) complexes: Cytotoxicity and cellular uptake of titanium(IV) complexes on caco-2 cell line

       Hernández, Ramón et al.

       Toxicology in Vitro, 24(1), 178 (Feb., 2010)

       Replacement of the ancillary ligand in titanocene dichloride by amino acids provides titanocene species with high water solubility. Authors have investigated the cytotoxic activity of Cp2TiCl2 and three water soluble titanocene-amino acid complexes - [Cp2Ti(aa)2]Cl2 (aa = l-cysteine, l-methionine, and d-penicillamine) and one water soluble coordination compound, [Ti4(maltolato)8([mu]-O)4] on the human colon adenocarcinoma cell line, Caco-2. At pH of 7.4 all titanocene species decompose extensively while [Ti4(maltolato)8([mu]-O)4] is stable for over seven days. In terms of cytotoxicity, the [Cp2Ti(aa)2]Cl2 and [Ti4(maltolato)8([mu]-O)4] complexes exhibited slightly higher toxicity than titanocene dichloride at 24 h, but at 72 h titanocene dichloride and [Ti4(maltolato)8([mu]-O)4] have higher cytotoxic activity. Cellular titanium uptake was quantified at various time intervals to investigate the possible relationship between Ti uptake and cellular toxicity. Results indicated that there was not a clear relationship between Ti uptake and cytotoxicity. A structure-activity relationship is discussed.

       Half-sandwich RuII[9]aneS3 complexes structurally similar to antitumor-active organometallic piano-stool compounds: Preparation, structural characterization and in vitro cytotoxic activity

       Bratsos, Ioannis et al.

       Journal of Inorganic Biochemistry, 102(5-6), 1120 (May 2008)

       The preparation, structural characterization, and chemical behavior in aqueous solution of a series of new Ru[9]aneS3 half-sandwich complexes of the type [Ru([9]aneS3)Cl(NN)][CF3SO3] and [Ru([9]aneS3)(dmso-S)(NN)][CF3SO3]2 (5-15, NN = substituted bpy or 2 × 1-methylimidazole) are described. The X-ray structures of [Ru([9]aneS3)Cl(3,3'-H2dcbpy)][CF3SO3] (9) (3,3'-H2dcbpy = 3,3'-dicarboxy-2,2'-bipyridine), [Ru([9]aneS3)Cl(4,4'-dmobpy)][CF3SO3] (13) (4,4'-dmobpy = 4,4'-dimethoxy-2,2'-bipyridine), and [Ru([9]aneS3)Cl(1-MeIm)2][CF3SO3] (15) (1-MeIm = 1-methylimidazole) were also determined. The new compounds are structurally similar to anticancer-active organometallic half-sandwich complexes of formula [Ru([eta]6-arene)Cl(NN)][PF6]. Three chloro compounds (5, 9, 15) were tested in vitro for cytotoxic activity against two human cancer cell lines in comparison with the previously described [Ru([9]aneS3)Cl(en)][CF3SO3] (1, en = ethylenediamine), [Ru([9]aneS3)Cl(bpy)][CF3SO3] (2), and with their common dmso precursor [Ru([9]aneS3)Cl(dmso-S)2][CF3SO3] (3). Only the ethylenediamine complex 1 showed some antiproliferative activity, ca. one order of magnitude lower than the reference organometallic half-sandwich compound RM175 that contains biphenyl instead of [9]aneS3. This compound was further tested against a panel of human cancer cell lines (including one resistant to cisplatin).

       Synthesis and characterisation of a ruthenocenoyl bioconjugate with the cyclic octapeptide octreotate

       Gross, Annika et al.

       Journal of Organometallic Chemistry, 694(7-8) 1185 (Apr., 1, 2009)

       The reaction of activated ruthenocene carboxylic acid with the resin-bound peptide octreotate yields, after cleavage and purification by preparative HPLC, the first ruthenocenoyl peptide bioconjugate 1. Octreotate is a chemically stabilized analogue of somatostatine. It is a cyclic octapeptide with a disulfide bond and has been previously used for molecular diagnostics due to the fact that somatostatine receptors are over-expressed by a variety of cancer cells. Conjugate 1 was obtained in good yield and purified by preparative HPLC to >95% purity as judged by analytical HPLC. It has been identified by HPLC, IR and mass spectrometry (ESI and MALDI-TOF). The peptide's NMR signals are assigned by standard 2D methods. In addition, the 1H NMR spectrum of 1 shows characteristic signals for the metallocene between 5.1 and 4.3 ppm. Compound 1 thus is a new example of tumor-targeted organometallic ruthenium bioconjugates.

       Ferrocenyl compounds possessing protected phenol and thiophenol groups: Synthesis, X-ray structure, and in vitro biological effects against breast cancer

       Heilmann, Julia B. et al.

       Journal of Organometallic Chemistry, 893(8-9), 1716 (Apr., 15, 2008)

       Authors have previously studied that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via metabolic quinone methide (QM) formation. To further evaluate this proposed mechanism, we have created a series of ferrocenyl prodrugs containing methyl and acetyl-protected thio- and oxo-phenols: 2-ferrocenyl-1,1-bis(4-acetoxyphenyl)-but-1-ene (5), 2-ferrocenyl-1,1-bis(4-thioacetylphenyl)-but-1-ene (6), 2-ferrocenyl-1,1-bis(4-methoxyphenyl)-but-1-ene (7), and 2-ferrocenyl-1,1-bis(4-thiomethylphenyl)-but-1-ene (8), which might be activated by hydrolysis enzymes in situ. Only the acetoxy 5 displayed antiproliferative effects (IC50 on MDA-MB-231 of 0.5 [mu]M) while 6-8 act as pure estrogens (proliferative on MCF-7 and little to no effect on MDA-MB-231). The behaviour of 5 is similar to that previously found for the free phenol 2-ferrocenyl-1,1-di(4-hydroxyphenyl)-but-1-ene (2), indicating that 5 is metabolized in situ to 2, which could then undergo oxidative QM formation. The observation that the thioacetyl 6 is not cytotoxic suggests that the in situ oxidative chemistry of the putative ferrocenyl thiophenol is different from that of 2. Because p-thioquinone methides are practically unknown, the negative results for 6 further implicate the bioformation of the QM in the case of 2 and related compounds. The lack of cytotoxicity of 7 and 8 can be attributed to lack of efficient hydrolysis in situ. Estrogen receptor binding affinity studies for the compounds and the X-ray structure of 8 are also reported.

       The replacement of a phenol group by an aniline or acetanilide group enhances the cytotoxicity of 2-ferrocenyl-1,1-diphenyl-but-l-ene compounds against breast cancer cells

       Pigeon, Pascal et al.

       Journal of Organometallic Chemistry, 694 (6), 895 (Mar., 15, 2009)

       Earlier studies have shown that conjugated ferrocenyl p-phenols show strong cytotoxic effects against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines, possibly via oxidative quinone methide formation. We now present a series of analogous amine and acetamide compounds: 2-ferrocenyl-1-(4-aminophenyl)-1-phenyl-but-1-ene (Z+E-2), 2-ferrocenyl-1-(4-N-acetylaminophenyl)-1-phenyl-but-1-ene (Z-3), and their corresponding organic molecules 1-(4-aminophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-4) and 1-(4-N-acetamidophenyl)-1,2-bis-phenyl-but-1-ene (Z+E-5). All of the compounds have adequate relative binding affinity values for the estrogen receptor; between 2.8% and 5.7% for ER[alpha], and between 0.18% and 15.5% for ER[beta], as well as exothermic ligand binding in in silico ER docking experiments. Compounds 2 and 3 show dual estrogenic/cytotoxic activity on the MCF-7 cell line; they are proliferative at low concentrations (0.1 [mu]M) and antiproliferative at high concentrations (10 [mu]M). On the MDA-MB-231 cell line, the ferrocenyl complexes 2 and 3 are antiproliferative with IC50 values of 0.8 [mu]M for 2 and 0.65 [mu]M for 3, while the purely organic molecules 4 and 5 show no effect. Electrochemical experiments suggest that both 2 and 3 can be transformed to oxidized quinoid-type species, analogous to what had previously been observed for the ferrocene phenols.

       Induction of apoptosis by hexaosmium carbonyl clusters

       Kong, Kien Voon et al.

       Journal of Organometallic Chemistry, 694 (6), 834 (Mar., 15, 2009)

       A number of tri- and hexaosmium carbonyl cluster derivatives were screened for cytotoxicity against five cancer cell lines, and the hexaosmium carbonyl clusters Os6(CO)18 and Os6(CO)16(NCCH3)2 were found to be active against four of these, viz., ER+ breast carcinoma (MCF-7), ER-breast carcinoma (MDA-MB-231), metastatic colorectal adenocarcinoma (SW620) and hepatocarcinoma (Hepg2), with IC50 values as low as 6 [mu]M. Studies on their mode of action with the MDA-MB-231 cell line pointed to the induction of apoptosis, as has been found earlier for the trinuclear cluster Os3(CO)10(NCCH3)2.

       Metals in anticancer therapy: Copper(II) complexes as inhibitors of the 20S proteasome

       Hindo, Sarmad Sahiel et al.

       European Journal of Medicinal Chemistry, 44(11), 4353 (Nov., 2009)

       Selective 20S proteasomal inhibition and apoptosis induction were observed when several lines of cancer cells were treated with a series of copper complexes described as [Cu(LI)Cl] (1), [Cu(LI)OAc] (2), and [Cu(HLI)(LI)]OAc (3), where HLI is the ligand 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol. These complexes were synthesized, characterized by means of ESI spectrometry, infrared, UV-visible and EPR spectroscopies, and X-ray diffraction when possible. After full characterization species 1-3 were evaluated for their ability to function as proteasome inhibitors and apoptosis inducers in C4-2B and PC-3 human prostate cancer cells and MCF-10A normal cells. With distinct stoichiometries and protonation states, this series suggests the assignment of species [CuLI]+ as the minimal pharmacophore needed for proteasomal chymotryspin-like activity inhibition and permits some initial inference of mechanistic information.

       Casiopeína IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells

       Kachadourian, Remy et al.

       Toxicology (In Press)

       Casiopeínas are a series of mixed chelate copper complexes that are being evaluated as anticancer agents. Their effects in the cell include oxidative damage and mitochondrial dysfunction, yet the molecular mechanisms leading to such effects remain unclear. Authors tested whether [Cu(4,7-dimethyl-phenanthroline)(glycinate)]NO3 (Casiopeína IIgly or Cas IIgly) could alter cellular glutathione (GSH) levels by redox cycling with GSH to generate ROS and cellular oxidative stress. Cas IIgly induced a dramatic drop in intracellular levels of GSH in human lung cancer H157 and A549 cells, and is able to use GSH as source of electrons to catalyze the Fenton reaction. In both cell lines, the toxicity of Cas IIgly (2.5-5 [mu]M) was potentiated by the GSH synthesis inhibitor l-buthionine sulfoximine (BSO) and diminished by the catalytic antioxidant manganese(III) meso-tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin (MnTDE-1,3-IP5+), thus supporting an important role for oxidative stress. Cas IIgly also caused an over-production of reactive oxygen species (ROS) in the mitochondria and a depolarization of the mitochondrial membrane. Moreover, Cas IIgly produced mitochondrial DNA damage that resulted in an imbalance of the expression of the apoproteins of the mitochondrial respiratory chain, which also can contribute to increased ROS production. These results suggest that Cas IIgly initiates multiple possible sources of ROS over-production leading to mitochondrial dysfunction and cell death.

       Bioactivity of novel transition metal complexes of N'-[(4-methoxy)thiobenzoyl]benzoic acid hydrazide

       Shrivastav, Anuraag et al.

       European Journal of Medicinal Chemistry, 43(3), 577 (Mar., 2008)

       Cu(II), Fe(III), and Mn(II) complexes of a novel ligand N'-[(4-methoxy) thiobenzoyl]benzoic acid hydrazide (H2mtbh) have been synthesized and characterized by elemental analyses, IR, UV-vis, NMR, mass, EPR and Mössbauer spectroscopy. The results suggest a square planar structure for [Cu(Hmtbh)Cl] and [Cu(mtbh)] whereas an octahedral structure for [Mn(Hmtbh)2] and [Fe(Hmtbh)(mtbh)]. Mn(II) and Fe(III) complexes were found to inhibit proliferation of HT29 cells. [Mn(Hmtbh)2] and [Fe(Hmtbh)(mtbh)] inhibited proliferation of HT29 cells with half maximal inhibition (IC50) of 8.15 ± 0.87 and 68.1 ± 4.8 [mu]M, respectively, whereas H2mtbh showed growth inhibition with IC50 of 90.9 ± 7.8 [mu]M and were able to inhibit NMT activity in vitro. Mn(II) and Fe(III) complexes inhibited NMT activity in a dose dependent manner with IC50 values of 20 ± 2.2 and 60 ± 7.2 [mu]M, respectively, whereas ligand (H2mtbh) displayed IC50 of 3.2 ± 0.5 mM.

       The tumor proteasome as a novel target for gold(III) complexes: Implications for breast cancer therapy

       Milacic, Vesna et al.

       Coordination Chemistry Reviews, 253 (11-12), 1649 (June 2009)

       Although cisplatin plays a vital role in the treatment of several types of human cancer, its wide use is limited by the development of drug resistance and associated toxic side effects. Gold and gold complexes have been used to treat a wide range of ailments for many centuries. In recent years, the use of gold(III) complexes as an alternative to cisplatin treatment was proposed due to the similarities of gold and platinum. Gold(III) is isoelectronic with platinum(II) and gold(III) complexes have the same square-planar geometries as platinum(II) complexes, such as cisplatin. Although it was originally thought that gold(III) complexes might have the same molecular target as cisplatin, several lines of data indicated that proteins, rather than DNA, are targeted by gold complexes. We have recently evaluated cytotoxic and anti-cancer effects of several gold(III) dithiocarbamates against human breast cancer cells in vitro and in vivo. Authors have identified the tumor proteasome as an important target for gold(III) complexes and have shown that proteasome inhibition by gold(III) complexes is associated with apoptosis induction in breast cancer cells in vitro and in vivo. Furthermore, treatment of human breast tumor-bearing nude mice with a gold(III) dithiocarbamate complex was associated with tumor growth inhibition, supporting the significance of its potential development for breast cancer treatment.

       Unusual DNA binding modes for metal anticancer complexes

       Pizarro, Ana M. et al.

       Biochimie, 91(10), 1198 (Oct., 2009)

       DNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes.

       Novel strategies for reversing platinum resistance.

       Shahzad, Mian M.K.

       Drug Resistance Updates, 12(6), 148 (Dec., 2009)

       Platinum-based drugs continue to be the mainstay of therapy for ovarian cancer. Along with adverse effects, chemoresistance (intrinsic or acquired) has become a major limitation in the management of recurrent disease. Even though much is known about the effects of platinum drugs on cancer cells, the mechanisms underlying resistance are poorly understood. In this review, we summarize the current data on chemoresistance and discuss novel strategies to reverse resistance to platinum-based drugs. The most important targets highlighted here include Aurora kinases, PARP, ATP7B, and ERCC1. Furthermore, we discuss the implications of these novel approaches for ovarian cancer treatment.

       Antiproliferative and anti-tumor activity of organotin compounds

       Hadjikakou, Sotiris K. et al.

       Coordination Chemistry Reviews, 253(1-2), 235 (Jan., 2009)

       Tin compounds and their therapeutic potentials are under consideration from many research groups, while a number of early reviews recording advances in the screening for antiproliferative potential of organotins are also available. This review focuses upon results obtained on the antiproliferative activity of tin compounds in the past 5 years.

       Anticancer drugs based on alkenyl and boryl substituted titanocene complexes

       Gómez-Ruiz, Santiago et al.

       Journal of Organometallic Chemistry, 694(13), 1981 (June 1, 2009)

       The alkenyl-substituted titanocene complex [Ti([eta]5-C5H5)([eta]5-C5H4{CMe2(CH2CH2CHCH2)})Cl2] (1) has been synthesized and characterized using traditional methods. The reaction of 1 with 9-BBN gave the boryl substituted complex [Ti([eta]5-C5H5)([eta]5-C5H4{CMe2(CH2CH2CH2CH2BC8H14)})Cl2] (2). The cytotoxic activity of 1 and 2 was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, human breast carcinoma MDA-MB-361 and normal immunocompetent cells peripheral blood mononuclear cells PBMC and compared with those of the reference complexes [Ti([eta]5-C5H5)2Cl2] (R1), [Ti([eta]5-C5H4Me)2Cl2] (R2) and [Ti([eta]5-C5H5)([eta]5-C5H4SiMe3)Cl2] (R3). Complex 1 showed higher cytotoxic activities on HeLa, Fem-x and K562 (IC50 values from 96.6 ± 3.4 to 149.2 ± 2.9 [mu]M) than the reference complexes R1, R2 and R3 which presented IC50 values from 173.3 ± 6.0 to >200 [mu]M. On the other hand, boryl substituted complex 2, present slightly lower cytotoxic activities than 1 on HeLa, Fem-x and K562 (IC50 values from 155.6 ± 5.5 to 167.9 ± 4.2 [mu]M). However, 2 was the most active of the studied complexes against MDA-MB-361 (IC50 value of 161.1 ± 0.1 [mu]M). Structural studies based on DFT calculations of 1 and 2 have also been carried out in order to gain a possible insight into the relationship between metal complex structure and cytotoxicity.

       Vanadium compounds as therapeutic agents: Some chemical and biochemical studies

       Faneca, H. et al.

       Journal of Inorganic Biochemistry, 103(4), 601(Apr., 2009)

       The behaviour of three vanadium(V) systems, namely the pyridinone (VV-dmpp), the salicylaldehyde (VV-salDPA) and the pyrimidinone (VV-MHCPE) complexes, is studied in aqueous solutions, under aerobic and physiological conditions using 51V NMR, EPR and UV-Visible (UV-Vis) spectroscopies. The speciations for the VV-dmpp and VV-salDPA have been previously reported. In this work, the system VV-MHCPE is studied by pH-potentiometry and 51V NMR. The results indicate that, at pH ca. 7, the main species present are (VVO2)L2 and (VVO2)LH-1 (L = MHCPE-) and hydrolysis products, similar to those observed in aqueous solutions of VV-dmpp. The latter species is protonated as the pH decreases, originating (VVO2)L and (VVO2)LH. All the VV-species studied are stable in aqueous media with different compositions and at physiological pH, including the cell culture medium. The compounds were screened for their potential cytotoxic activity in two different cell lines. The toxic effects were found to be incubation time and concentration dependent and specific for each compound and type of cells. The HeLa tumor cells seem to be more sensitive to drug effects than the 3T3-L1 fibroblasts. According to the IC50 values and the results on reversibility to drug effects, the VV-species resulting from the VV-MHCPE system show higher toxicity in the tumor cells than in non-tumor cells, which may indicate potential antitumor activity.

       Synthesis and characterisation of thiosemicarbazonato molybdenum(VI) complexes and their in vitro antitumor activity

       Vrdoljak, Visnja et al.

       European Journal of Medicinal Chemistry, 45(1), 38 (Jan.,2010)

       New dioxomolybdenum(VI) complexes were obtained by the reaction of [MoO2(acac)2] with thiosemicarbazone ligands derived from 3-thiosemicarbazide and 4-(diethylamino)salicylaldehyde (H2L1), 2-hydroxy-3-methoxybenzaldehyde (H2L2) or 2-hydroxy-1-naphthaldehyde (H2L3). In all complexes thiosemicarbazonato ligands are coordinated to molybdenum as tridentate ONS-donors. Octahedral coordination of each molybdenum atom is completed by methanol molecule (in 1a-3a) or by oxygen atom of MoO unit from the neighbouring molecule (in 1-3). All complexes were characterized by means of chemical analyses, IR spectroscopy, TG and NMR measurements. The molecular structures of the ligand H2L2 and complex [MoO2L2(CH3OH)]·CH3OH (2a) have been determined by single crystal X-ray crystallography. The characterisation of thiosemicarbazonato molybdenum(VI) complexes (1-4) as well as of the 4-phenylthisemicarbazonato molybdenum(VI) complexes (5-8) in aqueous medium revealed that upon dissolving complexes in water, most likely to some extent dissociation took place, although experimental data didn't allow exact quantification of dissociation. The antiproliferative effects of studied molybdenum(VI) complexes (1-8) on the human cell lines were identical to the activity of their corresponding ligands.

       Cytotoxic but show potent activity against Mycobacterium tuberculosis.

       Lauren C. Eiter  et al.

       J. Med. Chem., 2009, 52 (21), pp 6519–6522

       Cationic gold(I) complexes containing 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea (1), [AuL(1)]n+ (where L is Cl−, Br−, SCN−, PEt3, PPh3, or 1), derived from a class of analogous platinum(II) antitumor agents, have been synthesized. Unlike platinum, gold does not form permanent adducts with DNA, and its complexes are 2 orders of magnitude less cytotoxic in non-small-cell lung cancer cells than the most active platinum-based agent. Instead, several gold analogues show submicromolar and selective antimicrobial activity against Mycobacterium tuberculosis.

       Studies of the mechanism of action of platinum(II) complexes with potent cytotoxicity in human cancer cells

       Anwen M. Krause-Heuer  et al.

       J. Med. Chem., 2009, 52 (17), pp 5474–5484

       Authors have examined the biological activity of 12 platinum(II)-based DNA intercalators of the type [Pt(IL)(AL)]2+, where IL is an intercalating ligand (1,10-phenanthroline or a methylated derivative) and AL is an ancillary ligand (diaminocyclohexane, diphenyl-ethylenediamine or 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine). The chiral compounds (1−9) and the racemic compounds (10−12) were tested against a panel of human cancer cell lines, with a number of complexes displaying activity significantly greater than that of cisplatin (up to 100-fold increase in activity in the A-427 cell line). The activity of the complexes containing diphenylethylenediamine (8 and 9) and 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine (10−12) was significantly lower compared to the complexes containing diaminocyclohexane (1−7). Further in vitro testing, such as DNA unwinding, competition assays, and DNase 1 footprinting, was conducted on the most active compound (5) and its enantiomer (6) to provide information about the mechanism of action. These complexes display activity in cisplatin resistant cell lines, have higher cellular uptake than cisplatin, and do not activate caspase-3 as cisplatin does, indicating that these complexes exhibit a different mechanism of action.

       Cytotoxic activities, cellular uptake, gene regulation, and optical imaging of novel platinum(II) complexes.

       Jian Gao et al.

       Chem. Res. Toxicol., 2009, 22 (10), pp 1705–1712

       A new class of platinum(II) coordination complexes and their dye tagged conjugates has been synthesized from N-substituted diaminocyclohexane ligands. The in vitro anticancer activities of the platinum compounds have been validated against the breast cancer cell-line MCF-7 and the normal cell-line MCF-10A via sulforhodamine B and colony formation assay. The platinum compounds and the corresponding metal-free ligands exhibited higher drug efficiencies than cisplatin and oxaliplatin against MCF-7 cells. Cellular uptake and DNA-bound Pt were demonstrated by atomic absorption spectroscopy. The platinum complexes displayed increased cellular accumulation and DNA binding as compared with cisplatin. Real-time reverse transcription polymerase chain reaction assay was employed to investigate drug effects on mRNA expression in MCF-7 cells. The results indicated that the study compounds are effective in regulating cyclin D1, Bcl-2, and p53 genes; yet, oxaliplatin is less effective in manipulating those genes. The luminescent probe that was integrated into the platinum complexes made it possible to monitor cellular drug distribution using optical imaging. Targeting of tumor cell nuclei by the study compounds was confirmed by confocal microscopy. Taken together, these new platinum(II)-based antitumor agents are different from marketed platinum drugs in several critical aspects and could have potential in cancer therapy.

       Synthesis, cytotoxicity, and DNA interactions of new cisplatin analogues containing substituted benzimidazole ligands.

       Fatma GM  et al.

       J. Med. Chem., 2009, 52(5), pp 1345–1357

       Six new platinum(II) complexes with 1-H or methyl-2-chloromethyl or acetoxymethyl or 2′-hydroxyethylbenzimidazole carrier ligands were synthesized and evaluated for their reactivity against model nucleophile I−, cellular uptake, and in vitro antiproliferative activities against the human MCF-7 breast and HeLa cervix cancer cell lines. The effect of the compounds on pBR322 plasmid DNA was studied by gel electrophoretic mobility measurements. Flow cytometric analysis was also carried out to study the effect of representative compounds 1 and 2, bearing 2-chloromethyl or -acetoxymethylbenzimidazole carrier ligands, on the cell cycle distribution of MCF-7 and HeLa cells, respectively. In general, it was found that Pt(II) complexes were less cytotoxic than cisplatin and were comparable to carboplatin. The results of the plasmid DNA interaction and the restriction studies suggest that changing the chemical structure of the benzimidazole ligands may modulate DNA binding mode and the sequence selectivity. Compounds 1 and 2 had no significant effect on the cell cycle profile of the cells used. However, compound 2 induced a significant increase in the SubG1 cell population at a concentration of 20 μM.

       Photocytotoxic trans-diam(m)ine platinum(IV) diazido complexes more potent than their cis isomers.

       Nicola J. Farrer  et al.

       Chem. Res. Toxicol., 2010, 23(2), pp 413–421

       The photocytotoxicity of a series of anticancer trans-dihydroxido [Pt(N3)2(OH)2(NH3)(X)] (X = alkyl or aryl amine) platinum(IV) diazido complexes has been examined, and the influence of cis−trans isomerism has been investigated. A series of photoactivatable PtIV-azido complexes has been synthesized: The synthesis, characterization, and photocytotoxicity of six mixed-ligand ammine/amine PtIV diazido complexes, cis,trans,cis-[Pt(N3)2(OH)2(NH3)(X)] where X = propylamine (4c), butylamine (5c), or pentylamine (6c) and aromatic complexes where X = pyridine (7c), 2-methylpyridine (8c), or 3-methylpyridine (9c) are reported. Six all-trans isomers have also been studied where X = methylamine (2t), ethylamine (3t), 2-methylpyridine (8t), 4-methylpyridine (10t), 3-methylpyridine (9t), and 2-bromo-3-methylpyridine (11t). All of the complexes exhibit intense azide-to-PtIV LMCT bands (ca. 290 nm for trans and ca. 260 nm for cis). When irradiated with UVA light (365 nm), the PtIV complexes undergo photoreduction to PtII species, as monitored by UV−vis spectroscopy. The trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. One of the cis complexes (9c) was nonphotocytotoxic despite undergoing photoreduction. Substitution of NH3 ligands by MeNH2 or EtNH2 results in more potent photocytotoxicity for the all-trans complexes. The complexes were all nontoxic toward human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark, apart from the 3-methylpyridine (9t), 2-bromo-3-methylpyridine (11t), and 4-methylpyridine (10t) derivatives.

       Effects of polyamines on the DNA-reactive properties of dimeric mithramycin complexed with cobalt(II): implications for anticancer therapy.

       Ming-Hon Hou et al.

       Biochemistry, 2009, 48(22), pp 4691–4698

       Few studies have examined the effects of polyamines on the action of DNA-binding anticancer drugs. In this study, a Co(II)-mediated dimeric mithramycin (Mith) complex, (Mith)2−Co(II), was shown to be resistant to polyamine competition toward the divalent metal ion when compared to the Fe(II)-mediated drug complexes. Surface plasmon resonance experiments demonstrated that polyamines interfered with the binding capacity and association rates of (Mith)2−Co(II) binding to DNA duplexes, while the dissociation rates were not affected. Although (Mith)2−Co(II) exhibited the highest oxidative activity under physiological conditions (pH 7.3 and 37 °C), polyamines (spermine in particular) inhibited the DNA cleavage activity of the (Mith)2−Co(II) in a concentration-dependent manner. Depletion of intracellular polyamines by methylglyoxal bis(guanylhydrazone) (MGBG) enhanced the sensitivity of A549 lung cancer cells to (Mith)2−Co(II), most likely due to the decreased intracellular effect of polyamines on the action of (Mith)2−Co(II). Our study suggests a novel method for enhancing the anticancer activity of DNA-binding metalloantibiotics through polyamine depletion.

       Emerging protein targets for anticancer metallodrugs: inhibition of thioredoxin reductase and cathepsin B by antitumor ruthenium(II)−arene compounds

       Angela Casini et al.

       Med. Chem., 2008, 51(21), pp 6773–6781

       A series of ruthenium(II)−arene (RAPTA) compounds were evaluated for their ability to inhibit thioredoxin reductase (either cytosolic or mitochondrial) and cathepsin B, two possible targets for anticancer metallodrugs. In general, inhibition of the thioredoxin reductases was lower than that of cathepsin B, although selected compounds were excellent inhibitors of both classes of enzymes in comparison to other metal-based drugs. Some initial structure−activity relationships could be established. On the basis of the obtained data, different mechanisms of binding/inhibition appear to be operative; remarkably the selectivity of the ruthenium compounds toward solid metastatic tumors also correlates to the observed trends. Notably, docking studies of the interactions of representative RAPTA compounds with cathepsin B were performed that provided realistic structures for the resulting protein−metallodrug adducts.

       Interaction of metallothionein-2 with platinum-modified 5-guanosine monophosphate and DNA.

       Andrei V. Karotki et al.

       Biochemistry, 2008, 47(41), pp 10961–10969

       Human metallothioneins (MTs), a family of cysteine- and metal-rich metalloproteins, play an important role in the acquired resistance to platinum drugs. MTs occur in the cytosol and the nucleus of the cells and sequester platinum drugs through interaction with their zinc−thiolate clusters. Herein, authors investigate the ability of human Zn7MT-2 to form DNA−Pt−MT cross-links using the cisplatin- and transplatin-modified plasmid DNA pSP73. Immunochemical analysis of MT-2 showed that the monofunctional platinum−DNA adducts formed DNA−cis/trans-Pt−MT cross-links and that platinated MT-2 was released from the DNA−trans-Pt−MT cross-links with time. The DNA−cis/trans-Pt−MT cross-links were also formed in the presence of 2 mM glutathione, a strong S-donor ligand. Independently, we used 5′-guanosine monophosphate (5′-GMP) platinated at the N7 position as a model of monofunctional platinum−DNA adducts. Comparison of reaction kinetics revealed that the formation of ternary complexes between Zn7MT-2 and cis-Pt−GMP was faster than that of the trans isomer. The analysis of the reaction products with time showed that while the formation of ternary GMP−trans-Pt−MT complex(es) is accompanied by 5′-GMP release, a stable ternary GMP−cis-Pt−MT complex is formed. In the latter complex, a fast initial formation of two Pt−S bonds was followed by a slow formation of an additional Pt−S bond yielding an unusual Pt(II)S3N coordination with N7-GMP as the only N-donor ligand. The ejection of negligible zinc from the zinc−thiolate clusters implies the initial formation of Zn−(μ-SCys)−Pt bridges involving the terminal thiolate ligands. The biological implications of these studies are discussed.

       Synthesis, oxidant properties, and antitumoral effects of a heteroleptic palladium(II) complex of curcumin on human prostate cancer cells.

       Alessandra Valentini et al.

       J. Med. Chem., 2009, 52(2), pp 484–491

       A new ionic Pd(II) complex, [(bipy)Pd(Pcurc)][CF3SO3], 1, with the metal center coordinated to two different chelating ligands, the pure curcumin (Pcurc) and the 4,4′-dinonyl-2,2′-bipyridine (bipy), has been synthesized, fully characterized, and its antitumoral mechanism and oxidant property have been investigated. The Pd(II) complex induces both cell growth inhibition and apoptosis of human prostate cancer cells, (LnCaP, PC3, and DU145) through the production of ROS and JNK phosphorylation associated with GSTp1 down-regulation. ROS production induced by complex 1 treatment activated apoptotis through mitochondrial membrane depolarization in all prostate cancer cells, with up-regulation of Bax and down-regulation of Bcl-2 proteins. In addition, while curcumin determines DNA damage and PARP cleavage, complex 1 does not elicit any activation of PARP enzyme. Taken together, these data validate the significance of curcumin complexation to a metal center and its conjugation to another functionalized bioactive ligand in the apoptosis signal transduction and enhancement of cell death in prostate cancer cell lines and suggest the potential of this design strategy in the improvement of the metal-based drugs cytotoxicity.

       Catalysis and inhibition of Mycobacterium tuberculosis methionine aminopeptidase.

       Jing-Ping Lu et al.

       J. Med. Chem., 2010, 53(3), pp 1329–1337

       Methionine aminopeptidase (MetAP) carries out an important cotranslational N-terminal methionine excision of nascent proteins and represents a potential target to develop antibacterial and antitubercular drugs. Authors cloned one of the two MetAPs in Mycobacterium tuberculosis (MtMetAP1c from the mapB gene) and purified it to homogeneity as an apoenzyme. Its activity required a divalent metal ion, and Co(II), Ni(II), Mn(II), and Fe(II) were among activators of the enzyme. Co(II) and Fe(II) had the tightest binding, while Ni(II) was the most efficient cofactor for the catalysis. MtMetAP1c was also functional in E. coli cells because a plasmid-expressedMtMetAP1c complemented the essential function of MetAP in E. coli and supported the cell growth. A set of potent MtMetAP1c inhibitors were identified, and they showed high selectivity toward the Fe(II)-form, the Mn(II)-form, or the Co(II) and Ni(II) forms of the enzyme, respectively. These metalloform selective inhibitors were used to assign the metalloform of the cellular MtMetAP1c. The fact that only the Fe(II)-form selective inhibitors inhibited the cellular MtMetAP1c activity and inhibited the MtMetAP1c-complemented cell growth suggests that Fe(II) is the native metal used by MtMetAP1c in an E. coli cellular environment. Finally, X-ray structures of MtMetAP1c in complex with three metalloform-selective inhibitors were analyzed, which showed different binding modes and different interactions with metal ions and active site residues.

       Effects of metal coordination geometry on stabilization of human telomeric quadruplex DNA by square-planar and square-pyramidal metal complexes.

       Anna Arola-Arna et al.

       Inorg. Chem., 2008, 47(24), pp 11910–11919

       A series of square-planar and square-based pyramidal metal complexes (metal = Ni2+, Cu2+, Zn2+, and V4+) with salphen and salen derivatives as ligands have been prepared. The X-ray crystal structures of three of these complexes are reported, giving insight into the geometric properties of the compounds. The interactions of these complexes with duplex and human telomeric quadruplex DNA have been studied by fluorescence resonance energy transfer (FRET), fluorescent intercalator displacement assay, and in one case circular dichroism. These studies have shown the square-planar metal complexes to be excellent quadruplex DNA stabilizers. In addition, FRET competition assays have shown the complexes to have a high degree of selectivity for the DNA quadruplex versus duplex DNA. These studies have allowed us to establish the most important features that metal complexes should have to interact selectively with quadruplex DNA. This will be of value in defining the best strategy to prepare metal complexes as potential anticancer drugs.

       Rational design of highly cytotoxic η6-arene β-diketiminato−ruthenium complexes.

       Andrew D. Phillips et al.

       Organometallics, 2010, 29(2), pp 417–427

       A series of ruthenium−benzene complexes with β-diketiminate ligands modified with electron-withdrawing groups were prepared and characterized by NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. The complexes are stable in air and undergo controlled hydrolysis in water. The complexes were evaluated for anticancer activity in vitro, and two of them proved to be highly cytotoxic, comparable or even superior to cisplatin. This work shows the potential utility of the β-diketiminate ligand in the rational design of new anticancer metal-containing drugs. A related complex with a η6-C6H5CF3 ligand was prepared and found to undergo a nucleophilic addition reaction at the coordinated arene ring to afford a substituted η5-cyclohexadienyl derivative.

       Chemical and biological profiles of novel copper(II) complexes containing S-donor ligands for the treatment of cancer.

       Giovagnini L  et al.

       Inorg Chem.2008 Jul 21;47(14):6336-43.

       Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy.

       Authors have synthesized some new platinum(II), palladium(II), gold(I/III) complexes with dithiocarbamato derivatives as potential anticancer drugs, to obtain compounds with superior chemotherapeutic index in terms of increased bioavailability, higher cytotoxicity, and lower side effects than cisplatin. On the basis of the obtained encouraging results, authors have been studying the interaction of CuCl2 with methyl-/ethyl-/tert-butylsarcosine-dithiocarbamato moieties in a 1:2 molar ratio; authors also synthesized and studied the N, N-dimethyl- and pyrrolidine-dithiocarbamato copper complexes for comparison purposes. The reported compounds have been successfully isolated, purified, and fully characterized by means of several spectroscopic techniques. Moreover, the electrochemical properties of the designed compounds have been studied through cyclic voltammetry. In addition, the behavior in solution was followed by means of UV-vis technique to check the stability with time in physiological conditions. To evaluate their in vitro cytotoxic properties, preliminary biological assays (MTT test) have been carried out on a panel of human tumor cell lines. The results show that cytotoxicity levels of all of the tested complexes are comparable or even greater than that of the reference drug (cisplatin).

       Methylated bismuth, but not bismuth citrate or bismuth glutathione, induces cyto- and genotoxic effects in human cells in vitro.

       U. Von Recklinghausen  et al.

       Chem. Res. Toxicol., 2008, 21(6), pp 1219–1228

       Bismuth compounds are widely used in industrial processes and products. In medicine, bismuth salts have been applied in combination with antibiotics for the treatment of Helicobacter pylori infections, for the prevention of diarrhea, and in radioimmunotherapy. In the environment, bismuth ions can be biotransformed to the volatile bismuth compound trimethylbismuth (Me 3Bi) by methanobacteria. Preliminary in-house studies have indicated that bismuth ions are methylated in the human colon by intestinal microflora following ingestion of bismuth-containing salts. Information concerning cyto- and genotoxicity of these biomethylated products is limited. In the present study, we investigated the cellular uptake of an organic bismuth compound [monomethylbismuth(III), MeBi(III)] and two other bismuth compounds [bismuth citrate (Bi-Cit) and bismuth glutathione (Bi-GS)] in human hepatocytes, lymphocytes, and erythrocytes using ICP-MS. We also analyzed the cyto- and genotoxic effects of these compounds to investigate their toxic potential. Our results show that the methylbismuth compound was better taken up by the cells than Bi-Cit and Bi-GS. All intracellularly detected bismuth compounds were located in the cytosol of the cells. MeBi(III) was best taken up by erythrocytes (36%), followed by lymphocytes (17%) and hepatocytes (0.04%). Erythrocytes and hepatocytes were more susceptible to MeBi(III) exposure than lymphocytes. Cytotoxic effects of MeBi(III) were detectable in erythrocytes at concentrations >4 µM, in hepatocytes at >130 µM, and in lymphocytes at >430 µM after 24 h of exposure. Cytotoxic effects for Bi-Cit and Bi-GS were much lower or not detectable in the used cell lines up to a tested concentration of 500 µM. Exposure of lymphocytes to MeBi(III) (250 µM for 1 h and 25 µM/50 µM for 24 h) resulted in significantly increased frequencies of chromosomal aberrations (CA) and sister chromatid exchanges (SCE), whereas Bi-Cit and Bi-GS induced neither CA nor SCE. Our study also showed an intracellular production of free radicals caused by MeBi(III) in hepatocytes but not in lymphocytes. These data suggest that biomethylation of bismuth ions by the intestinal microflora of the human colon leads to an increase in the toxicity of the primary bismuth salt.

       Flexible porous metal-organic frameworks for a controlled drug delivery.

       Patricia Horcajada  et al.

       J. Am. Chem. Soc., 2008, 130(21), pp 6774–6780

       Flexible nanoporous chromium or iron terephtalates (BDC) MIL-53(Cr, Fe) or M(OH)[BDC] have been used as matrices for the adsorption and in vitro drug delivery of Ibuprofen (or α-p-isobutylphenylpropionic acid). Both MIL-53(Cr) and MIL-53(Fe) solids adsorb around 20 wt % of Ibuprofen (Ibuprofen/dehydrated MIL-53 molar ratio = 0.22(1)), indicating that the amount of inserted drug does not depend on the metal (Cr, Fe) constitutive of the hybrid framework. Structural and spectroscopic characterizations are provided for the solid filled with Ibuprofen. In each case, the very slow and complete delivery of Ibuprofen was achieved under physiological conditions after 3 weeks with a predictable zero-order kinetics, which highlights the unique properties of flexible hybrid solids for adapting their pore opening to optimize the drug-matrix interactions.

       Zinc(II)-coordinated oligotyrosine: a new class of cell penetrating peptide.

       James R. Johnson et al.

       Bioconjugate Chem., 2008, 19(5), pp 1033–1039

       A new series of cell penetrating peptides (CPPs) are described. The peptides are oligomers of Tyr-ZnDPA, a tyrosine derivative with an appended 2,2′-dipicolylamine unit that forms a very stable coordination complex with a zinc (II) cation. This in turn allows reversible association with a chelating oxyanion such as a carboxylate or phosphate derivative. The peptide oligomers (Tyr-ZnDPA)n where n = 1, 2, 4, 8, are highly water soluble, but upon association with fatty acids or phospholipids they partition into an organic octanol phase. Furthermore, a fluorescent, fluorescein-labeled version of the octamer, (Tyr-ZnDPA)8-Fl, can enter living mammalian cells via endocytosis and a biotin derivative can deliver fluorescein-labeled streptavidin. Fluorescence microscopy and flow cytometry experiments show that cell uptake is diminished by conditions that inhibit endocytosis. Additionally, uptake of (Tyr-ZnDPA)8-Fl is greater than fluorescein labeled octaarginine (Arg8-Fl) in all cell lines tested (CHO, COS-7, HeLa). Another difference with Arg8-Fl is that cell uptake of (Tyr-ZnDPA)8-Fl does not require the presence of heparan sulfate proteoglycans on the cell surface. This difference may eventually be of practical value because drug delivery systems that employ alternative endocytic mechanisms may be optimal for different cell lines or they may deliver selectively to different organelles within a cell.

       Design of HIV protease inhibitors based on inorganic polyhedral metallacarboranes.

       Pavlna ez ov et al.

       J. Med. Chem., 2009, 52(22), pp 7132–7141

       HIV protease (HIV PR) is a primary target for anti-HIV drug design. Authors have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, authors connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H2N-(8-(C2H4O)2-1,2-C2B9H10)(1′,2′-C2B9H11)-3,3′-Co)2]Na. Authors explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. These results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.

       Hydrolytic metal with a hydrophobic periphery: titanium(IV) complexes of naphthalene-2,3-diolate and interactions with serum albumin.

       Arthur D. Tinoco  et al.

       Inorg. Chem., 2008, 47(18), pp 8380–8390

       Serum albumin, the most abundant protein in human plasma (700 μM), binds diverse ligands at multiple sites. While studies have shown that serum albumin binds hard metals in chelate form, few have explored the trafficking of these metals by this protein. Recent work demonstrated that serum albumin may play a pivotal role in the transport and bioactivity of titanium(IV) complexes, including the anticancer drug candidate titanocene dichloride. The current work explores this interaction further by using a stable Ti(IV) complex that presents a hydrophobic surface to the protein. Ti(IV) chelation by 2,3-dihydroxynaphthalene (H2L1) and 2,3-dihydroxynaphthalene-6-sulfonate (H2L2) affords water soluble complexes that protect Ti(IV) from hydrolysis at pH 7.4 and bind to bovine serum albumin (BSA). The solution and solid Ti(IV) coordination chemistry were explored by aqueous spectropotentiometric titrations and X-ray crystallography, respectively, and with complementary electrochemistry, mass spectrometry, and IR and NMR spectroscopies. Four Ti(IV) species of L2, TiLH0, TiL2H0, TiL3H0, and TiL3H−1, adequately represent the pH-dependent speciation. The isolation of Ti(C10H6O2)2·1.75H2O at pH~3 and K2[Ti(C10H6O2)3]·3H2O and Cs5[Ti(C10H5O5S)3]·2.5H2O at pH~7 correlates well with the solution studies. At pH 7.4 and micromolar concentrations, the TiL3H0 species are favored. The Ti(naphthalene-2,3-diolate)32− complex binds with moderate affinity to multiple sites of BSA. The primary site (K = 2.05 ± 0.34 × 106 M−1) appears to be hydrophobic as indicated by competition studies with different ligands and a hydrophilic Ti(IV) complex. The Ti(naphthalene-2,3-diolate)32− interaction with the Fe(III)-binding protein human serum transferrin (HsTf), a protein also important for Ti(IV) transport, and DNA was examined. The complex does not deliver Ti(IV) to HsTf and while it does bind to DNA, no cleavage promotion activity is observed. This investigation provides insight into the use of ligands to direct metal binding at different sites of albumin, which may facilitate transport to distinct targets.

       Solution chemistry of copper(II)− gentamicin complexes: relevance to metal-related aminoglycoside toxicity.

       Wojciech Lesniak et al.

       Inorg. Chem., 2003, 42 (5), pp 1420–1429

       The adverse effect to the inner ear of aminoglycosides, drugs widely administered for the treatment of serious infections, appears to result from the interaction of these drugs with Cu(II) or Fe(II)/Fe(III) ions. To understand more completely the metal-induced side effects of one such antibiotic, gentamicin, we studied copper(II) coordination to gentamicin C1a by potentiometry, UV−vis, CD, and EPR spectroscopies, and ESI mass spectrometry. Only monomeric complexes of the CuHnL stoichiometry, with n ranging from 3 to −2, were detected over the pH range of 4−12. CuH3L and CuH2L complexes exhibit the same coordination mode, binding copper(II) through the amino nitrogen atom and a deprotonated alcoholic oxygen atom of the garosamine ring. In the CuHL and CuL complexes a second amino nitrogen atom of the purpurosamine ring participates in central ion coordination. Finally, the additional axial binding of the deprotonated oxygen of the hydroxyl group of the 2-deoxystreptamine moiety occurs in the CuH-1L and CuH-2L complexes. Interactions of the Cu(II)−gentamicin−H2O2 system at pH 7.4 with N,N-dimethyl-p-nitrosoaniline, arachi-donic acid, and plasmid DNA confirmed that gentamicin complexes facilitate oxidative reactions leading to peroxidation of arachidonic acid and scission of double-stranded DNA mediated by copper-bound reactive oxygen species. However, the stability constants of Cu(II)−gentamicin complexes are inferior to the binding constants of copper(II) complexes with other components of human serum or cells. Computer simulations of copper(II) distribution in the human blood plasma showed that the concentration of gentamicin would have to be at impossible levels (100 M) before a significant fraction of Cu(II) ions would be bound to gentamicin. Further, once introduced into aqueous solution, histidine replaces gentamicin in Cu(II)−gentamicin complexes. Therefore, Cu(II)−gentamicin complexes might not exist under physiological conditions.










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1.      Place of Publication                                           :  Lucknow

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Organometallic Compounds in Oncology: Implications of Novel Organotins as AntitumorAgents


       Since the introduction of cisplatin in cancer therapy, metal complexes and organometallic compounds have been gaining growing importance in oncology. The impressive clinical effectiveness of cisplatin is limited by significant side effects and the emergence of drug resistance. Thus, novel classic and unconventional PtII and PtIV complexes have been introduced in therapy or are presently in advanced clinical trials. Moreover, innovative non-platinum metal-based antitumor agents, whose activity does not rely on direct DNA damage and may involve proteins and enzymes, have been developed. Gold and tin derivatives are enjoying an increasing interest and appear very promising as potential drug candidates.

Metal-based compounds in therapy

       Metal-based compounds were largely present in old pharmacopoeias, side by side with raw drugs of natural (vegetal and animal) origin. Because of their limited selectivity and toxicity, metal derivatives were progressively neglected in favor of the more reliable organic compounds, either synthetic or isolated in pure form from natural sources. Thus, the number of metal-based drugs decreased steadily, even if novel forms and/or novel therapeutic indications for some of them have been introduced in the medical use. Nowadays some derivatives of three elements of group Va (As, Sb, Bi), as melarsaprol (for the late stages of African trypanosomiasis), sodium stibogluconate (for leishmaniasis and other protozoal infections), and bismuth citrate or subsalicylate (for traveler's diarrhea and Helicobacter pylori eradication) are worth of mention. To these, silver sulfadiazine and auranofin, containing metals of group Ib, should be added. The former still represents an agent of choice for the prevention of burn infections, while the latter, once highly valuable for the treatment of rheumatoid arthritis is being replaced by immunosuppressant and cytokine receptor antagonists. Finally, lithium carbonate or citrate, largely used in the past as a diuretic and (even if inappropriately) to solubilize urate deposits, is currently a mainstay for the treatment of mania and the prophylaxis of bipolar disorders.

       The serendipitous discovery by Rosenberg in 1965 of the antiproliferative activity of a platinum complex  recognized ascis-diamminedichloroplatinum (cisplatin) and its subsequent successful introduction in the therapy of testicular cancer, fostered a renewed and growing interest in metal-based drugs, particularly organometallic complexes, as antitumor agents. Indeed, a very impressively high cure-rate, was observed with cisplatin.

       The cis-diamminedichloroplatinum was firstly prepared by Michele Peyrone professor of chemistry at the University of Genoa. This compound, originally known as ‘Peyrone's salt’, was of fundamental interest in the development of the ‘coordination theory’ for which Alfred Werner earned the Nobel Prize in 1913.

       Metal-based compounds enlarge the possibility of building up molecules better suited for binding to specific biological targets. Indeed, metal ions exhibit a wide range of coordination numbers and geometries, which allow to organize the most different anions and organic ligands (with their chemical and biological properties) in more appropriate spatial distributions, affording better modalities of attack to the target molecules.

       Moreover, the redox potential of the metal can interact with the balanced cellular redox state, modifying cell viability either directly or through the conversion of a rather inert compound in an activated one, thus tuning the inherent toxicity of the drug.

Cisplatin and other platinum complexes in the therapy of cancer

       Cisplatin is among the most active anticancer agents, producing DNA damage similar to alkylating agents. Its cytotoxic mechanism of action consists of activation through an aquation reaction involving the exchange of the two chloride leaving groups with water or hydroxyl ligands.  The water molecules then exchange with nitrogens and sulfurs of proteins and nucleic acids with a preference for the N-7 positions of adenine and guanine of DNA. Intrastrand coordination bond lesions, as well as other bifunctional lesions in DNA, are then formed. If the lesions occur on the same DNA strand and bases are adjacent, they are referred to as DNA adducts. If the sites are on different strands, the lesions are known as interstrand crosslinks. All of these injuries lead to inhibition of enzymes involved in RNA transcription, DNA replication and chain elongation of DNA polymerization.

       The clinical effectiveness of cisplatin is, however, greatly limited by drug resistance and significant side effects that are the main factors responsible for recurrence and morbidity. Indeed, while some tumors exhibit intrinsic resistance to cisplatin, others develop acquired resistance after a few courses of treatment.

       The development of less toxic, but equally effective, cisplatin analogs has been strongly pursued and a huge number of platinum compounds have been prepared and screened as potential antitumor agents over the past 30 years. Nearly 40 complexes have been investigated in clinical trials up to now; of these, only carboplatin and oxaliplatin have been approved for clinical use in 1989 and 2003, respectively. 

       At present, cisplatin, carboplatin, and oxaliplatin are the only metal-based anticancer agents soundly established in clinic and are found in a large number (>50%) of chemotherapeutic regimens (Figure 1).

       Indeed, as a group, these complexes exhibit a broad antineoplastic spectrum and, in combination with other chemotherapeutic agents, can be highly effective in testicular, ovarian, colorectal, cervix, and lung cancers. Oxaliplatin is particularly active in combination with 5-FU in the treatment of advanced gastro-intestinal tumors. It is worth noting that carboplatin is better tolerated than cisplatin in vivo and, despite a rather poor activity in in vitro assays, is a valid alternative drug for different malignancies in patients unable to tolerate cisplatin. This observation calls for more careful evaluation criteria of novel drugs, in order to avoid prematurely discarding potentially useful compounds with only modest activity in vitro. 

       Cell resistance to cisplatin and its analogs is associated with upregulation of DNA repair, but also with the capture and inactivation of the complex by macromolecular blood components and/or thiol-containing reductants that might modulate the sensitivity of cells to























Figure 1. Chemical structures of platinum(II) and (IV) complexes.

the drug.  In an attempt to overcome this issue, novel PtII (as thioplatin and picoplatin and  PtIV (as satraplatin and ethacraplatin complexes have been developed. The sterically hindered PtII complex, picoplatin, which is under active clinical investigation against non-small cell lung cancer exhibits reduced reactivity toward biomolecules and lower susceptibility to inactivation that allow this drug to be administered orally. Similarly, reduced reactivity and oral bioavailability is observed in the octahedrally coordinated PtIV complexes, which need to be reduced to planar PtII complexes to exert cytotoxicity. Satraplatin seems to offer several advantages over the standard i.v. platinum drugs, especially in hormone refractory prostate cancer 

       Furthermore, the development of agents forming radically different adducts to DNA as the all-trans trinuclear platinum complexes BBR3464 and triplatinNC may help overcome resistance to cisplatin (Figure 1). These compounds strongly associate with DNA, either by long-range crosslinks or by binding to oxygen atoms of the phosphate. The former was up to 100-fold more potent than cisplatin against some resistant cell lines, but in clinical trials exhibited disappointing results Triplatin NC showed enhanced cellular uptake, despite the high positive charge (8+), and could play an interesting role as a carrier device capable of delivering drugs to DNA 

       Finally, it is worth mentioning a UVA-photoactivated trans PtIVcomplex that, differing from classic porphyrin photosensitizers, does not require oxygen to kill cancer cells (Figure 1). Therefore, its application in photodynamic therapy of hypoxic malignant tumors appears to be a reasonable hypothesis 

Non-platinum metal compounds as antitumor drugs

       Though the cisplatin molecular motif has led to the discovery of such successful drugs as
























Figure 2. Chemical structures of ruthenium, iron, cobalt, and gallium complexes.


carboplatin and oxaliplatin, further significant improvement in metal-based cancer therapy might be achieved from the study of platinum complexes of unconventional structures, such as those mentioned above, and from non-platinum metal compounds. Indeed, Bell described the systemic use of colloidal lead to treat cancer in humans in 1924 and later, in 1929, Collier presented results on organolead and organotin compounds in experimental mouse cancer. 

       Following the Second World War, the chemistry of coordination compounds and the availability of stable organo-metals prompted the investigation of a growing number of metal compounds with potential cytotoxicity. Several thousand compounds, derived from about thirty metals, have been prepared and tested and some of them are now in phase II and III clinical trials. In particular, those elements belonging to group VIIIb of the periodic table, to which platinum belongs, have been preferentially studied. As information on such compounds increased, attention became mainly focused on ruthenium, iron, and cobalt (Figure 2).


       Ruthenium complexes appear particularly promising despite exhibiting lower cytotoxicity compared to cisplatin, they are better tolerated in vivo. RuIII complexes maintain the metal oxidation state until they reach the tumor, where the low oxygen level permits their activation by reduction to RuII. The antitumor activity of ruthenium complexes involves binding to DNA, but additional mechanisms are also possible. The strong binding capacity for albumin and transferrin markedly influences the biodistribution of these complexes. Of great interest is their characteristic inhibition of angiogenesis and matrix metalloproteinases and, hence, metastasis in vivo.

       The most interesting RuIII complexes are KP418, KP1019, and NAMI-A (Figure 2).


       Simple ferricenium salts were the first iron complexes exhibiting some antitumor activity. Recently, ferrocene derivatives of tamoxifen, a selective estrogen receptor modulator, have been described as antiproliferative compounds. In ferrocifen a ferrocene moiety replaces the unsubstituted phenyl residue of the active metabolite of tamoxifen. This molecule is able to act on both estrogen receptor expressing (ER+) and non-expressing (ER−) human breast cancer cell lines. The activity of ferrocifen arises from the peculiar redox properties of the FeII complex that initiates the chain of reactions leading to the formation of a quinone methide susceptible to nucleophilic attack from biomolecules. Another aspect of the impact of iron on cancer therapy is the formation of active species from the union of the iron ion with chemotherapeutic agents, such as bleomycin, to produce activated species of oxygen responsible for DNA breakdown 

       Moreover, the administration of iron chelators, such as desferrioxamine, together with cisplatin, etoposide, or doxorubicin has a synergistic effect, either through the formation of cytotoxic complexes or by the deprivation of iron to the cell itself.


       Hexacarbonyl dicobalt and alkynes form peculiar complexes where the triple bond character is lost. They exhibit antiproliferative activity against several human cancer cell lines (particularly breast). The activity is most remarkable when the alkyne is the propargylic ester of aspirin (CoASS) Indeed, it has been shown that CoASS itself inhibits COX-1 and COX-2 more strongly than aspirin. Since cyclooxygenase inhibition retards the growth of established tumors and enhances their response to conventional therapies it is likely that Co-ASS may exert its antiproliferative activity        through     a     dual   mechanism.





























Figure 3. Chemical structures of gold complexes.



       Of the elements of the main groups of the periodic table, gallium occupies an important position Gallium (III) exhibits coordination characteristics similar to Fe3+, but differs from the latter being redox-inactive in cellular environments.

       At present, two complexes, gallium 8-quinolinolate (KP46) and gallium maltolate (Figure 2), administered via the oral route, are under evaluation in the clinical setting The mechanism of action of gallium is mainly related to the inhibition of ribonucleotide reductase (RR), which catalyses the conversion of ribonucleotides to desoxyribonucleotides. The association of gallium derivatives with different inhibitors of RR (as, for instance, 1-formylisoquinoline thiosemicarbazone) produces highly potent antiproliferative complexes. 

Gold and tin compounds

       Of the non-platinum metal compounds with antitumor activity, particular interest has been focused on gold and tin derivatives, which have a common activity on mitochondria and a strong affinity to thiol groups of proteins and enzymes. 


       Gold thiolates have been used for a long time in the therapy of rheumatoid arthritis interestingly, treated patients exhibited a lower rate of malignancy than the age-matched and sex-matched general population. Indeed auranofin (but not sodium aurothiomalate) exhibited potent in vitro cytotoxicity against a number of tumor cell lines (Figure 3).

       The importance of the presence of a phosphine ligand was soon recognized and other gold(I) complexes with triethylphosphine, triphenylphosphine, 1,2-bis(diphenylphosphine)ethane (dppe), and so on, were prepared and found to be active in in vitro and in vivo assays. 

       The tetrahedral complex, [Au(dppe)2]Cl, demonstrated particular efficacy in several cancer models (Figure 3) but exhibited cardiotoxicity in rabbits and severe hepatotoxicity in dogs. 

       Studies with chloro (triethylphosphine) gold (I), [Au(dppe)2]Cl, and auranofin showed that mitochondria are the targets of gold complexes. Indeed, gold displays a high electrophilic affinity for thiols and inhibition of mitochondrial human glutathione reductase (hGR) and thioredoxin reductase (hTrxR) has been demonstrated. The thioredoxin system provides the reducing equivalents for ribonucleotide reductase to form desoxyribonucleotides and is, therefore, involved in the process of cell division. Mammalian ThxRs are selenoenzymes, incorporating selenocysteine as the penultimate aminoacid. Micromolar concentrations of gold are required to inhibit GR, while even nanomolar concentrations are capable of affecting TrxR.

       Phosphol-containing gold complexes (Figure 3) have been shown to inhibit both hGR and hTrxR at 0.8–7 nM concentrations but display antiproliferative activity in glioblastoma cell lines with IC50/ID50 (drug concentration or dose reducing survival by 50% vs.control) in the range 5.4–15.2 μM. 

       The thioredoxin system is involved in the formation and regeneration of methylselenol, which is responsible for detoxifying the reactive oxygen species that initiate cancer formation. On the contrary, increased expression of Trx is often associated with aggressive tumor growth and resistance to traditional treatment modalities.  In order to improve the selectivity of [Au(dppe)2]Cl complex for cancer cells over normal cells, molecular lipophilicity was lowered by exchanging phenyl residues for pyridines (that can be protonated and are, therefore, more hydrophilic) or introducing carboxylic groups on the ethylene chains. 

       The 2-pyridylphosphine analog, which is endowed with moderate lipophilicity and cation character, was very active against murine subcutaneous colon 38 tumors, whereas the second type of analogs, whose anionic character prevented their access to the negatively charged matrix of tumor cell mitochondria, were inactive. Very promising compounds, with novel lipophilic cationic characteristics, have been obtained by replacing the phosphine ligands with N-heterocyclic carbene ligands, obtained from dialkylimidazolinium salts. To balance the lipophilic–hydrophilic character of phosphine-gold(I) complexes, the metal valence was also saturated with aminothiolate anions, whose lipophilicity may be enhanced by increasing the number of carbon atoms, while hydrophilicity is conferred by the protonable nitrogen. Available data concerning eight compounds, derived from diethylaminoethanethiol, 1-methylpiperazine-4-ethanethiol and from the bulky bicyclic, highly lipophilic, and strongly basic lupinylthiol [(1R,9aR)-octahydro-2H-quinolizine-1-methanethiol], seemed to confirm this assumption. The compounds containing triphenylphosphine or 1,2-bis(dimethylphosphine)ethane as ligands were moderately or poorly active, while the others exhibited good activity against human ovarian cancer cell lines compared to cisplatin. 

       Several gold (III) complexes have also been studied and proved to be extremely active when containing appropriate ligands to stabilize the oxidation state. Despite being isoelectronic and isostructural to square planar PtII complexes, they weakly interact with DNA but inhibit thioredoxin reductase. 


       Early studies, in 1929, on the cytotoxic activity of organotin (IV) derivatives produced contradictory results.  Later, in 1972, it was shown that triphenyltin acetate (but not the corresponding chloride) retarded tumor growth in mice.  Since then, a huge number of organotin derivatives have been prepared and tested in vitro and in vivo, firstly, against murine leukemia cell lines and, after that, against different panels of human cancer cell lines. Many organotin compounds are widely available, since they have found a variety of industrial and agricultural applications and are suitable as starting materials for the synthesis of novel derivatives. Moreover, organotins have been extensively studied as environmental toxicants since they are well known for their potent biocidal action. Most of the compounds tested early on, exhibited interesting activity in specific cancer models, but they often lacked activity against a broad spectrum of experimental tumors. Nevertheless, the large possibility for variation of the organic moieties and donor ligands linked to the metal has resulted in several diorganotin and triorganotin (IV) compounds with high antiproliferative activity in vitro against a variety of solid and hematologic cancers. In solution, triorganotin compounds may undergo spontaneous disproportionation into the corresponding diorganotin and tetraorganotin derivatives while, in vivo, the loss of one alkyl or aryl group may occur through the intervention of enzymes such as aromatase. 

       On the basis of the above consideration, diorganotin compounds might be considered to be the ultimate cytotoxic agents and the frequently observed higher activity of triorganotins may be related to pharmacokinetic considerations.

       Inhibition of macromolecular synthesis, mitochondrial energy metabolism, and reduction of DNA synthesis, as well as direct interaction with the cell membrane (increase in cytosolic Ca2+concentration), have been implicated in organotin-induced cytotoxicity In addition, promotion of oxidative and DNA damage in vivo has been detected Both oxidative damage and increased concentration of intracellular calcium ions seem to be the major factors contributing to triorganotin-induced apoptosis in many cell lines. Increased histone      acetyltransferase       activity     and




























Figure 4. Chemical structures of diorganotin and triorganotin derivatives.


activation of retinoid X receptor and PPARγ may play additional roles in the antiproliferative activity of organotins. Besides halides (Cl, Br) or pseudohalides (SCN), most organotin compounds contain carboxylic acid residues as exchangeable groups (Figure 4). Triorganotin carboxylates may exist in monomeric or polymeric forms, while diorganotin derivatives may exist as true dicarboxylates or as distannooxane salts [(R2SnOCOR’)2O] and may further aggregate in a number of ways that influence both solubility and bioavailability. Among all, diorganotin and triorganotin terebates and lithocolates (Figure 4), tested against a panel of seven human cancer cell lines, were found to be highly active and more potent than cisplatin with ID50 values in the range <3–134 ng/ml (<4.5–245 nM). Sulfur-containing ligands (which may represent widely differing chemical structures) appear particularly suitable to fulfil this task although, in some cases, the leaving group might be released too slowly for activity to be seen. Triphenyltin(IV) pyrimidine thiolate and diphenyltin(IV) 5-chloro-2-benzothiazole thiolate were the most active among a number of analogs against rat sarcoma cells. Besides IC50 values in the submicromolar range, an interesting correlation between cytotoxicity and inhibition of lipooxygenase-induced peroxidation of linoleic acid was also reported. Within a set of ten di(4-cyanobenzyl)tin(IV) dithiocarbamates, very high activity against five human tumor cell lines was observed. The highest activity was shown by the complex (4-NC–C6H4–CH2)2Sn(Cl)S2C–N(CH2CH2)2N–CH3 against MCF-7 and IGROV cells, with IC50 values of 14 and 19.3 nM, respectively. Furthermore, the complex triphenyltin 2-(triphenyltinmercapto)nicotinate exhibited an IC50 as low as 0.005 μg/ml (5.5 nM) against leiomyosarcoma. tert-Aminoalkylthiols have not received much attention as ligands to address the solubility issue so often encountered with organotin derivatives.

       Moreover, while IST-FS 29 was very active in vivo in murine tumor models (P388 myelomonocytic leukemia, B16-F10 melanoma and 3LL Lewis lung carcinoma), after repeated oral administrations, IST-FS 35 was able to inhibit the tumor growth of implanted P388 and B16-F10 cells, by up to 96%, after a single i.v. injection. Since IST-FS 35 produced peritoneal irritation via the i.p. route and did not appear to be well absorbed orally, i.v. administration was considered as the treatment of choice. No important signs of toxicity were observed with either compound, and autoptical and histological examinations confirmed their mild toxicity. Therefore, these compounds appear as potential drug candidates and deserve further development inin vivo preclinical setting in the perspective of their clinical application.


       Very important progress in medicinal organo-metallic chemistry has been seen in the past few years, allowing the rational design of novel, non-conventional, platinum compounds, as well as innovative non-platinum metal-based antitumor agents. Ruthenium and gallium are drug candidates of high relevance, but gold and tin derivatives, which, in the 1990s were not considered serious candidates as antitumor drugs, are now enjoying resurgence and, indeed, appear very promising as potential drugs. As a consequence of their mechanism of action, targeting macromolecular synthesis, mitochondrial energy metabolism, and DNA, gold and tin derivatives may result in compounds that are particularly active against cisplatin-resistant cancers.

(Based on the article written by Angela Alama and published in Drug Discovery Today, Vol. 14, No. 9/10, May 2009)


       In vivo tumour and metastasis reduction and in vitro effects on invasion  assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model.

       Bergamo, A. et al.

       Journal of Inorganic Biochemistry, 104(1), 79 (Jan., 2010)

       Authors have compared the organometallic arene complexes [([eta]6-biphenyl) M(ethylene-diamine)Cl]+ RM175 (M = RuII) and its isostructural osmium(II) analogue AFAP51 (M = OsII) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6× more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231 cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo.

       Pathophysiologic correlation between 62Cu-ATSM and 18F-FDG in lung cancer.

       Lohith TG  et al.

       J Nucl Med. 2009 Dec;50(12):1948-53. Epub 2009 Nov 12.

       The purpose of this study was to delineate the differences in intratumoral uptake and tracer distribution of (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((62)Cu-ATSM), a well-known hypoxic imaging tracer, and (18)F-FDG in patients with lung cancer of pathohistologically different types.: Eight patients  with squamous cell carcinoma (SCC) and 5 with adenocarcinoma underwent (62)Cu-ATSM and (18)F-FDG PET within a 1-wk interval. For (62)Cu-ATSM PET, 10-min static data acquisition was started at 10 min after a 370- to 740-MBq tracer injection. After image reconstruction, (62)Cu-ATSM and (18)F-FDG images were coregistered, and multiple small regions of interest were drawn on tumor lesions  of the 2 images to obtain standardized uptake values (SUVs). The regression lines were determined between SUVs for (62)Cu-ATSM and (18)F-FDG in each tumor. The slope values were compared between SCC and adenocarcinoma to observe pathohistologic differences in intratumoral distribution of the tracers.: SUVs for (62)Cu-ATSM were lower than those for (18)F-FDG in both SCC and adenocarcinoma. SCC tumors showed high (62)Cu-ATSM and low (18)F-FDG uptakes in the peripheral region of tumors but low (62)Cu-ATSM and high (18)F-FDG uptakes toward the center (spatial mismatching). The relationship of SUVs for the 2 tracers was negatively correlated with a mean regression slope of -0.07  0.05.On the other hand, adenocarcinoma tumors had a spatially similar distribution of  (62)Cu-ATSM and (18)F-FDG, with positive regression slopes averaging 0.24  0.13. The regression slopes for (62)Cu-ATSM and (18)F-FDG differed significantly between SCC and adenocarcinoma (P < 0.001).: The intratumoral distribution patterns of (62)Cu-ATSM and (18)F-FDG were different between SCC and adenocarcinoma in lung cancers, indicating that intratumoral regions of high glucose metabolism and hypoxia could differ with the pathohistologic type of lung cancer. The identification of regional biologic characteristics in tumors such as hypoxia, energy metabolism, and proliferation could play a significant role in the clinical diagnosis and therapy planning for non-small cell lung cancer patients.







       Synthesis and antitubercular activity of palladium and platinum complexes with fluoroquinolones.

       Vieira LM et al.

       Eur J Med Chem. 2009 Oct;44(10):4107-11. Epub 2009 May 15

       The fluoroquinolones are an important family of synthetic antimicrobial agents being clinically used over the past thirty years. In addition, some fluoroquinolones have been used in the development of anticancer drugs, and others have demonstrated anti-HIV activity. Furthermore, there has been some additional work investigating the effect of metal ions on biological activity. Aiming to obtain novel palladium(II) and platinum(II) complexes that exhibit biological activity, researchers have synthesized complexes using fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin, and gatifloxacin) as ligands. The compounds were characterized using IR and NMR spectroscopy, thermogravimetric and elemental analyses. The complexes show activity against Mycobacterium tuberculosis strain H(37)Rv. The minimal inhibitory concentration (MIC) of the complexes was determined.

       Organometallic SERMs (selective estrogen receptor modulators): Cobaltifens, the (cyclobutadiene)cobalt analogues of hydroxytamoxifen

       Nikitin, Kirill et al.

       Journal of Organometallic Chemistry, 695 (4), 595 (Feb., 15, 2010)

       The McMurry coupling of (tetraphenylcyclobutadiene)cobalt(cyclopentadienyl) ketones, (C4Ph4)Co[C5H4C(O)R], where R = Me, 3a, or Et, 3b, with a range of substituted benzophenones furnished a series of cobaltifens, organometallic analogues of tamoxifen whereby a phenyl ring has been replaced by an organo-cobalt sandwich moiety. These systems of the general formula ([eta]4-C4Ph4)Co[[eta]5-C5H4C(R)C(Ar)Ar'], where R = Me or Et, and Ar = Ar' = p-C6H4X where X is OH, 2a and 2b, OMe, 2c and 2d, OBn, 2e and 2f, or O(CH2)2NMe2, 12a and 12b, and where Ar = C6H4OH and Ar' = C6H4O(CH2)2NMe2, 2g and 2h, have been characterised by NMR spectroscopy and/or X-ray crystallography. The effect of 2a and 2b, 2g and 2h, and 12a and 12b on the growth of MCF-7 (hormone-dependent) and MDA-MB-231 (hormone-independent breast cancer cells) was studied. The dihydroxycobaltifens 2a and 2b exhibit a strong estrogenic effect on MCF-7 cells while the aminoalkyl-hydroxycobaltifens, 2g and 2h, were found to be only slightly cytotoxic on MDA-MB-231 cells (IC50 = 27.5 and 17 [µ]M); however, the bis-(dimethylamino-ethoxy)cobaltifens, 12a and 12b were shown to be highly cytotoxic towards both cell lines (IC50 = 3.8 and 2.5 [mu]M).

       Some O,O’,O’’,O’’’-di/tetra aryldithio-imidophonate transition metal complexes derived from catechol and bisphenol-A as antibacterial and antifungal agents.

       Vikrant Kumar et al.

       European Journal of Medicinal Chemistry 44 (2009) 785e793

       Two new substituted-thioimidophonate derivatives H1L1 -diaryldithio-imidophonates) and H1L2 (-tetra aryldithioimidophonates) were synthesized. These thioimidophonates are potential ligands towards transition metal ions. The reaction of M(II) acetates (M(II) Ľ Mn(II), Co(II), Ni(II), Cu(II), and Zn(II)) with H1L1 and H1L2 resulted in the formation of solid complexes with the composition (L1/L2)2M(II). These compounds were characterized through elemental analysis, electrical conductance, infrared, electronic spectra, nmr, magnetic susceptibilities etc. Vibrational mode assignments of n(PN), n(PS), n(MS), phenyl and methyl group bands are made. Structural and bonding changes are correlated with these vibrational frequencies. All the compounds were screened for their antibacterial and antifungal properties and have exhibited potential activities with MIC (0.09e1.50 mg/ml).

       A novel manganese complex effective as superoxide anion scavenger and therapeutic agent against cell and tissue oxidative injury.

       Failli, Paola  et al.

       Journal of Medicinal Chemistry, 52(22), 7273 (Oct., 27, 2009)

       Two cyclic polyamine-polycarboxylate ligands, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H2L3) and 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H2L4), and two noncyclic scaffolds, N-(2-hydroxyethyl)ethylenediamine-N,N′,N′-triacetic acid (H3L1) and ethylene-bisglycol-tetracetic acid (H4L2), form stable complexes with Mn(II) in aqueous solutions. Cyclic voltammograms show that the complexes with the most hydrophobic ligands, [MnL2]2− and [MnL4], are oxidized at higher potential than [MnL1]− and [MnL3]. The pharmacological properties of these molecules were evaluated as superoxide ion scavengers and anti-inflammatory compounds. Among the four complexes, [MnL4] was the most bioactive, being effective in the nanomolar/micromolar range. It abates the levels of key markers of oxidative injury on cultured cells and ameliorates the outcome parameters in animal models of acute and chronic inflammation. [MnL4] toxicity was very low on both cell cultures in vitro and mice in vivo. Hence, authors have proposed [MnL4] as a novel stable oxygen radical scavenging molecule, active at low doses and with a low toxicity.

       Enhancement of the antimalarial activity of ciprofloxacin using a double prodrug/bioorganometallic approach.

       Dubar F et al.

       J Med Chem. 2009 Dec 24;52(24):7954-7.

       The derivatization of the fluoroquinolone ciprofloxacin greatly increases its antimalarial activity by combining bioorganometallic chemistry and the prodrug approach. Two new achiral compounds 2 and 4 were found to be 10- to 100-fold more active than ciprofloxacin against Plasmodium falciparum chloroquine-susceptible and chloroquine-resistant strains. These achiral derivatives killed parasites more rapidly than did ciprofloxacin. Compounds 2 and 4 were revealed to be promising leads, creating a new family of antimalarial agents.

       Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs.

       Bindoli, Alberto et al.

       Coordination Chemistry Reviews, 253 (11-12) 1692 (June 2009)

       The thioredoxin system plays a key role in regulating the overall intracellular redox balance. Several lines of evidence point out today that the thioredoxin system represents an effective "druggable" target for the development of new anticancer agents. Accordingly, a number of established anticancer agents were retrospectively found to be potent inhibitors of thioredoxin reductases and to induce severe oxidative stress. During the last decade a variety of gold compounds, either gold(I) or gold(III), were reported to manifest outstanding antitumor properties, forming a promising class of experimental anticancer agents. In turn, recent studies have revealed that several cytotoxic gold compounds, either gold(I) or gold(III), are potent TrxR inhibitors. Details of their mechanism of selenoenzyme inhibition are currently under investigation, in our laboratory, and some new results will be anticipated here; notably, preferential gold targeting of active site selenolate could be experimentally supported. Based on the numerous experimental evidences now available, both at the molecular and cellular level, authors propose that the relevant cytotoxic actions produced by gold compounds are mainly the result of potent inhibition of thioredoxin reductase; the alterations of mitochondrial functions, elicited by profound TrxR inhibition, would eventually lead to cell apoptosis. A general and unitary framework is thus offered to interpret the mode of action of cytotoxic gold compounds, according to which they should be primarily considered as antimitochondrial drugs. The peculiar properties of gold compounds highlighted in this review might be further exploited for the obtainment of newer and selective anticancer agents.

       Vanadium complexes with thiosemicarbazones: Synthesis, characterization, crystal structures and anti-Mycobacterium tuberculosis activity.

       da S. Maia, Pedro I. et al.

       Polyhedron,28(2) 398(Feb., 3, 2009)

       The development of more efficient anti-tuberculosis drugs is of interest. Three oxovanadium(IV) and three cis-dioxovanadium(V) complexes with thiosemicarbazone derivatives bearing moieties with different lipophilicity have been prepared and had their inhibitory activity against Mycobacterium tuberculosis H37Rv ATCC 27294 evaluated. The analytical methods used by the complexes' characterization included IR, EPR, 1H, 13C and 51V NMR spectroscopies, elemental analysis, cyclic voltammetry, magnetic susceptibility measurement and single crystal X-ray diffractometry. [VO(acac)(aptsc)], [VO(acac)(apmtsc)] and [VO(acac)(apptsc)] (acac=acetylacetonate; Haptsc=2-acetylpyri-dinethiosemicarbazone; Hapmtsc = 2-acetyl-pyridine-N(4)-methyl-thiosemicarbazone and Happtsc = 2-acetylpyridine-N(4)-phenyl-thiosemicarbazone) are paramagnetic and their EPR spectra are consistent with the monoanionic N,N,S-tridentate coordination of the thiosemicarbazone ligands, resulting in octahedral structures of rhombic symmetry and with the oxidation state +IV for the vanadium atom. As result of oxidation of the vanadium(IV) complexes above, the diamagnetic cis-dioxovanadium(V) complexes [VO2(aptsc)], [VO2(apmtsc)] and [VO2(apptsc)] are formed. Their 1H, 13C and 51V NMR spectra were acquired and support a distorted square pyramidal geometry for them, in accord with the solid state X-ray structures determined for [VO2(aptsc)] and [VO2(apmtsc)]. In general, the vanadium compounds show comparable or larger anti-M. tuberculosis activities than the free thiosemicarbazone ligands, with MIC values within 62.5-1.56 ([µ]g/mL).

       Novel benzyl-substituted vanadocene anticancer drugs.

       Gleeson, Brendan et al.

       Journal of Organometallic Chemistry, 694(9-10) 1369 (Apr., 15, 2009)

       From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(3,4-dimethoxyphenyl) fulvene (1b) and 6-(3,4,5-trimethoxyphenyl) fulvene (1c) with LiBEt3H, lithiated cyclopentadienide intermediates (2a-c) were synthesised. These intermediates were then transmetallated to vanadium with VCl4 to yield the benzyl-substituted vanadocenes bis-[(p-methoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3a), bis-[(3,4-dimethoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3b), and bis-[(3,4,5-trimethoxybenzyl)cyclopentadienyl] vanadium(IV) dichloride (3c). The two vanadocenes 3a and 3c were characterised by single crystal X-ray diffraction. All three vanadocenes had their cytotoxicity investigated through MTT based preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC50 values and compare them with the corresponding titanocene dichloride derivatives. Vanadocenes 3b-c were found to have IC50 values of 9.1 and 8.3 [µ]M, while 3a showed a superior value of 3.0 [µ]M, respectively.

       Novel metal complexes of boronated chlorine 6 for photodynamic therapy.

       Ol'shevskaya, Valentina A. et al.

       Journal of Organometallic Chemistry, 694 (11), 1632 (May 1, 2009)

       Various structural modifications of chlorins are aimed at optimization of biomedical characteristics of these plant-derived tetrapyrrolic compounds. In particular, conjugation with boron polyhedra improves the efficacy of chlorin e6 derivatives as antitumor photosensitizers. To obtain the compounds that may possess several clinically favorable characteristics, authors synthesized a series of metal chlorin e6 conjugates with 1-carba-closo-dodecaborate anion that contain Pd(II), Sn(IV) or Zn(II) in the coordination sphere of the chlorin macrocycle. The compounds were synthesized by alkylation of amino group in chlorin e6 metal complexes with 1-trifluoromethanesulfonylmethyl-1-carba-closo-dodecaborate cesium. The water soluble Pd(II) complex of chlorin e6 13(1)-N-{2-[N-(1-carba-closo-dodecaboran-1-yl)methyl]aminoethyl}amide-15(2), 17(3)-dimethyl ester (compound 6) evoked low dark cytotoxicity; in striking contrast, 6 potently sensitized human tumor cells to illumination with monochromatic red light. Confocal microscopic studies demonstrated that photoactivation of 6 rapidly (within minutes) changed the patterns of intracellular drug distribution from diffuse cytoplasmic to clustered perinuclear. Co-localization experiments revealed that 6 associated with lysosomes in illuminated cells. These events were paralleled by alteration of mitochondrial shape, a decrease of mitochondrial transmembrane electric potential and the loss of plasma membrane impermeability for propidium iodide, the latter being a hallmark of cell necrosis. Similar mechanisms of cell photodamage were found for structurally close Pd(II) complex of chlorin with neutral carborane and for Sn(IV) chlorin conjugated with the anionic carborane. Thus, metal complexes of carboranylchlorins are efficient photosensitizers capable of triggering rapid necrosis. These compounds are promising for further development as multipotent agents in which each moiety, i.e., metal, the chlorin macrocycle and the boron substituent, as well as the entire complex, can be useful in cancer diagnostics and treatment.

       A novel iron-chelating derivative of the neuroprotective peptide NAPVSIPQ shows antioxidant and antineurodegenerative capabilities.

       Dan Biat et al.

       J Med Chem., 2008 Jan 10; 51(1):126-34.

       Affecting an estimated 5% of adults over 65 years of age, Parkinson's disease and Alzheimer's disease are the most common neurodegenerative disorders. Accumulating evidence suggests that oxidative stress induced by the breakdown of iron homeostasis is a major contributor to the neuronal loss observed in neurodegeneration. Thus, brain-permeable iron chelators may present potential therapeutic benefits. In the present study, iron-chelating hydroxamate groups were introduced into the NAP (NAPVSIPQ) peptide, whose neuroprotective qualities have been widely demonstrated. The experiments revealed that the novel dihydroxamate peptide 3 is capable of inhibiting iron-catalyzed hydroxyl radical formation and lipid peroxidation, abilities that are not part of the repertoire of its parent peptide. In addition, peptide 3 was superior to native NAP in protecting human neuroblastoma cell cultures against the toxicity of hydrogen peroxide. These results suggest that NAP-based iron chelators deserve further investigation in the search for drug candidates for neurodegeneration.













       Biologically active compounds of semi-metals

       Rezanka, Tomás et al.

       Phytochemistry, 69(3), 585 (Feb., 2008)

       Semi-metals (boron, silicon, arsenic and selenium) form organo-metal compounds, some of which are found in nature and affect the physiology of living organisms. They include, e.g., the boron-containing antibiotics aplasmomycin, borophycin, boromycin, and tartrolon or the silicon compounds present in "silicate" bacteria, relatives of the genus Bacillus, which release silicon from aluminosilicates through the secretion of organic acids. Arsenic is incorporated into arsenosugars and arsenobetaines by marine algae and invertebrates, and fungi and bacteria can produce volatile methylated arsenic compounds. Some prokaryotes can use arsenate as a terminal electron acceptor while others can utilize arsenite as an electron donor to generate energy. Selenium is incorporated into selenocysteine that is found in some proteins. Biomethylation of selenide produces methylselenide and dimethylselenide. Selenium analogues of amino acids, antitumor, antibacterial, antifungal, antiviral, anti-infective drugs are often used as analogues of important pharmacological sulfur compounds. Other metalloids, i.e. the rare and toxic tellurium and the radioactive short-lived astatine, have no biological significance.

       Biological activity of metal ions complexes of chromones, coumarins and flavones

       Grazul, Magdalena et al.

       Coordination Chemistry Reviews, 253(21-22), 2588(Nov., 2009)

       The medical properties of naturally occurring compounds such as chromones, flavonoids and coumarins have been well known for many years. However, the discovery that their complexes with metal ions are more effective than coumarins and flavonoids alone changed the course of drug research. Numerous studies showed that these complexes can be successfully used in a range of diseases such as diabetes mellitus, some bacterial infections or even cancers. In this account their role in the treatment of neurodegenerative diseases, like Huntington's disease, or in preventing conditions like heavy metal poisoning is discussed. The complexes can also influence the equilibrium of iron within a living organism, which is an important factor in the treatment of diseases like Friedreich ataxia and [beta]-thalassemia.









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Bacterium transforms toxic gold compounds to their metallic form.

       Australian scientists have found that the bacterium Cupriavidus metallidurans catalyses the biomineralisation of gold by transforming toxic gold compounds to their metallic form using active cellular mechanism. Researchers reported the presence of bacteria on gold surfaces but have never clearly elucidated their role. Now, an international team of scientists has found that there may be a biological reason for the presence of these bacteria on gold grain surfaces.

       “A number of years ago it was discovered that the metal-resistant bacterium Cupriavidus metallidurans occurred on gold grains from two sites in Australia. The sites are 3500 km apart, in southern New South Wales and northern Queensland, so when the same organism found on grains from both sites was thought it was onto something. It made us wonder why these organisms live in this particular environment. The results of this study point to their involvement in the active detoxification of Au complexes leading to formation of gold biominerals,” explains Frank Reith, leader of the research and working at the University of Adelaide (Australia).

       The experiments showed that C. metallidurans rapidly accumulates toxic gold complexes from a solution prepared in the lab. This process promotes gold toxicity, which pushes the bacterium to induce oxidative stress and metal resistance clusters as well as an as yet uncharacterized Au-specific gene cluster in order to defend its cellular integrity. This leads to active biochemically-mediated reduction of gold complexes to nano-particulate, metallic gold, which may contribute to the growth of gold nuggets.

       This is the first direct evidence that bacteria are actively involved in the cycling of rare and precious metals, such as gold. These results open the doors to the production of biosensors.

       “The discovery of an Au-specific operon means that it can now start to develop gold-specific biosensors, which will help mineral explorers to find new gold deposits. To achieve this, it is necessary  to further characterize the gold-specific operon on a genomic as well as proteomic level.

ScienceDaily (Oct. 9, 2009) 



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       Bioconjugates of metal complexes of nitrogen-containing macrocyclic ligands  

       Neumann William l et al.

       Inotek Pharmaceuticals, Massachusetts, US

       US2009098047, 2009-04-16

       The invention is directed to bioconjugates of complexes  for use as contrast agents in diagnostic imaging.  

       Production process of glucosamine lysine selenium salt 

       Xiulan Peng

       Xiulan Peng , China

       CN101095689, 2008-01-02

       The invention discloses a method for preparing aminoglucose lycine selenium salt, which comprises aminoglucose preparation, aminoglucose selenite preparation, and reaction of aminoglucose leading to final products selenite and lycine. The selenium salt complex is produced with bivalent monohydrate selenium dioxide anion with aminoglucose and lycine.

       Combination of intercalating organometallic complexes and tumor seeking biomolecules for DNA cleavage and radiotherapy.

       Alberto; Roger Ariel  et al.

       University of Zurich, Switzerland .

       US Patent  7,582,295 September 1, 2009 Appl. No.: 10/707,994 January 30, 2004

       The invention relates to molecules for treatment and diagnosis of tumors and malignancies, comprising a tumor seeking biomolecule, which is coupled to an intercalating moiety, which is capable of complexing a metal, which metal is preferably a radioactive metal, to the use of these molecules and to therapeutic and diagnostic compositions containing them.

       Phosphine transition metal complex, method for producing the same, and antitumor agent containing the same.

       Kodama; Hiroaki et al

       Nippon Chemical Industrial Co., Ltd., Tokyo, Japan

       US Patent  7,655,810 February 2, 2010 Appl. No.: 12/096,316 November 30, 2006

       A phosphine transition metal complex is expressed by general formula (1):










##STR00001## wherein A represents a groups selected from among alkylene, phenylene, and cis-vinylene; M represents an atom selected from the group consisting of gold, silver, copper, and platinum; B.sup.1 and B.sup.2 each represent a substituted or unsubstituted heterocyclic group containing a trivalent phosphorus atom forming a covalent bond with A and coordinating with M; and C represents an anionic atom.

       Anti-tumor composition

       Morinaga; Yoshihiro et al.

       Ajinomoto Co., Inc., Tokyo, Japan

       US Patent  7,655,696 February 2, 2010 Appl. No.: 11/196,454 August 4, 2005

       The invention provides composition having as active ingredients a stilbene derivatively and a platinum coordination compound which is highly efficacious and highly safe for treating tumors, particularly for the treatment of solid or malignant tumors and thus methods of cancer and tumor treatment using the composition are also provided.

       Combinations comprising epothilones and pharmaceutical uses thereof

       Rothermel; John David et al.

       Novartis AG, Basel, Switzerland

       US Patent  7,612,052 November 3, 2009 Appl. No.: 12/019,294 January 24, 2008

       The invention relates to a combination which comprises (a) a bisphosphonate, a platinum compound or a vasculostatic compound and (b) an epothilone wherein A represents O or NR.sub.N, wherein R.sub.N is hydrogen or lower alkyl, R is hydrogen or lower alkyl, and Z is O or a bond, in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use, in particular for the delay of progression or treatment of a proliferative disease, especially a solid tumor disease; a pharmaceutical composition, a commercial package or product comprising such a combination; the use of such a combination for the preparation of a medicament for the delay of progression or treatment of a proliferative disease and to a method of treatment of a warm-blooded animal.

       Process for the preparation of an anti-tumor platinum (II)--complex

       Maikap; Golak Chandra et al.

       Fresenius Kabi Oncology Limited, New Delhi, India

       US Patent  7,608,730 October 27, 2009 Appl. No.: 10/588,397 February 5, 2004

       Authors have  disclosed the processes for making Platinum complex wherein, the conformation of 1,2-diaminocyclohexane is cis, trans-l or trans-d isomer and R.sub.1 and R.sub.2 combinedly make dicarboxylic acid having formulae (II), (III) and (IV), here in, the two carboxylic acid groups are on the same or on vicinal carbon atoms, n is zero or an integer ranging from 1 to 5 and R.sub.3 is either hydrogen or a substituent with electron withdrawing or electron releasing effects exemplified by alkoxy, halo, and nitro groups by reacting a compound of formula M.sub.2PtX.sub.4 wherein X represents halogen atom such as Cl or Br or thiocyanate with (i) 1,2-diaminocyclohexane (ii) source of silver ion selected from a silver compound containing divalent anion in presence of a corresponding carboxylic acid of formula (II) or (III) or (IV) to get the compound of formula (I), purifying the said compound by treating with alkali metal iodide and isolating the title compound by any conventional methods. The preparation of the said compound involves, for the first time, the intermediate formation of cis-Diiodo-trans-l-1,2-diaminocyclohexane platinum(II) and biscarboylato-trans-l-1,2-diaminocyclo-hexane platinum(II).

       Targeted bisplatinum polyamines as pro-drugs: selective release of platinum

       Farrell; Nicholas et al.

       Virginia Commonwealth University, Richmond, Virginia, US

       US Patent 7,579,373 August 25, 2009 Appl. No.: 10/225,436 August 22, 2002

       Pro-drug forms of linear polyamine-bridged platinum compounds and methods for their production and use are provided. The polyamine-bridge portion of the compounds is based on spermine or spermidine, and the central amines of the polyamine-bridge are chemically bonded to labile blocking groups. The presence of the blocking groups serves to minimize the toxicity of the Pt compounds upon administration. Selective removal of the blocking groups and release of the active, unblocked species occurs upon exposure to suitable environmental conditions.

       Platinum (II) complexes, preparation and use

       Du Preez; Jan Gysbert Hermanus et al.

       Platco Technologies (Proprietary) Limited, Port Elizabeth, South Aferica

       US Patent  7,576,126 August 18, 2009 Appl. No.: 10/580,425 November 24, 2004

       The invention relates to a method for the preparation of platinum (II) complexes, in particular dicarboxylatoplatinum (II) complexes containing a neutral bidentate ligand, such as oxaliplatin. The method includes the step of reacting a bis-dicarboxylatoplatinate (II) species with a suitable neutral bidentate ligand to form a neutral dicarboxylatoplatinum (II) complex and, if necessary, recrystallising the product to form a pure dicarboxylatoplatinum (II) complex containing a neutral bidentate ligand.

       Bi-functional metallocenes, preparation process and use in the labeling or biological molecules

       Chaix-Bauvais Carole et al.

       Bio Merieux, Marcy l'Etoile, France

       US Patent  7,301,041 November 27, 2007 Appl. No.: 10/501,347 February 14, 2003

       Metallocenes are known as labels for oligonucleotides, in particular for the detection of DNA or RNA fragments. The invention relates to bi-functionalised metallocenes of general formula (I) where Me=a transition metal, preferably chosen from Fe, Ru and Os, Y and Z, when identical are selected from --(CH.sub.2).sub.n--O--, (CH.sub.2)--O--[(CH.sub.2).sub.2--O].sub.P-- and --(CH.sub.2).sub.q--CONH--(CH.sub.2).sub.r--O--, or Y=--(CH.sub.2).sub.S--NH-- and Z=--(CH.sub.2).sub.t--COO--, .sub.n=a whole number from 3 to 6 inclusive, p=a whole number from 1 to 4 inclusive, q=a whole number from 0 to 2 inclusive, r=a whole number from 0 to 2 inclusive, s=a whole number from 2 to 5 inclusive, t=a whole number from 3 to 6 inclusive, R and R'=H atoms or are protective groups used in oligonucleotide and peptide synthesis, where at least one of R or R' is protective group used in oligonucleotide and peptide synthesis and R and R' are as defined below: (i) when Z and Y are selected from (CH.sub.2).sub.n--O--, --(CH.sub.2)--O--[(CH.sub.2).sub.2--O].sub.p-- and --(CH.sub.2).sub.q--CONH--(CH.sub.2).sub.r--O--, then R and R' are protective groups used in oligonucleotide synthesis and R is a group which can leave a free OH group after deprotection, preferably a photolabile group such as monomethroxythoxytrityl, dimethoxytrityl, t-butyldimethylsilyl, acetyl or trifluroacetyl, and R' is a phosphorylated group which can react with a free OH, preferably a phosphodiester, phosphoramidite or H-phosphonate and (ii)







when Y=--(CH.sub.2).sub.s--NH-- and Z=--(CH.sub.2).sub.t--COO--, then R is a protective group used in the synthesis of peptides and is an amino-protecting group, preferably 9-fluorenyloxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl and R'=H. The above is applied in marking.

       Organometallic skeleton compounds on the basis of triptycene.

       Bahnmüller, Stefan; et al.

       Bayer Materialscience AG, Germany

       WO/2009/098001 13.08.2009

       The invention relates to organometallic skeleton compounds on the basis of triptycene derivatives, in particular 9,10 triptycene dicarboxylate, and to a method for the production of said compounds.

       An efficient process to induce enantioselectivity in procarbonyl compounds

       Babu, Bollu, Ravindra; et al.

       Aptuit Laurus Pvt Ltd; 3rd Floor, Uma Hyderabad House, Rajbhavan Road, Somajiguda, Hyderabad,  India

       WO/2009/095931 06.08.2009

       An efficient method to induce the enantioselectivity in procarbonyl compounds using chiral organometallic complexes. The present invention is also described a method for producing organo metallic complexes using a base and a metal halide.

       Hybrid nanoparticles as anti-cancer therapeutic agents and dual therapeutic/imaging contrast agents

       Lin, Wenbin; et al.

       The University of North Carolina , North Carolina, US

       WO/2009/139939 19.11.2009

       The invention provides information about nanoscale coordination polymers for use as anticancer agents and as dual anticancer/imaging agents. The nanoscale coordination polymers can comprise a plurality of platinum metal complexes; nonplatinum anticancer drug bridging ligands complexed to multiple metal centers; or combinations thereof. The nanoscale coordination polymers can be targeted for delivery to cancer cells. They can also comprise stabilizing agents to allow for controlled and/or sustained release of anticancer agents in vivo.

       Metal coordination complexes of volatile drugs

       Hale, Ron L et al.

       Alexza Pharmaceuticals, Inc. US

       WO/2009/089550 16.07.2009

       The disclosure provides a drug delivery device comprising a housing defining an airway, wherein the airway comprises at least one air inlet and a mouthpiece having at least one air outlet, at least one heated metal substrate disposed within the airway, at least one drug disposed on the at least one heated metal substrate. Drugs that can be complexed with metals or metal salts and could be deposited as thin films on heated metal substrate for generating thermal condensation aerosols are particularly suited. The metal substrate could be electrically or chemically heated. Further, the chemically heated metal source could be activated by an igniter that generates heat or spark.

       Silicon-containing compounds for treatment or prevention of bone loss or restoration of bone mass, or augmentation of bone mass.

       Bains, William Arthur et al.

       Opal Drug Discovery Limited, Great Britain

       WO/2008/152388 18.12.2008

       This invention describes compounds of the Formula (I) which are selective prostaglandin E2 receptor agonists and their use in treating diseases characterised by bone loss, or prevention of bone loss, or restoration of bone mass, or augmentation of bone mass.







       Preparation of siloxy-bridged metallocenes.

       Schiendorfer, Michael

       Basell Polyolefine GmbH, Germany

       WO/2009/149906 17.12.2009

       A method for making siloxy-bridged ligand precursors and metallocene complexes is disclosed. lndanone enolates react with cyclopentadienylsilyl compounds to produce ligand precursors, which are reacted with a Group 3-10 transition metal source to generate metallocene complexes. The method provides simple, regioselective access to particular siloxy-bridged metallocenes starting from easily elaborated indanones.