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  Reproductive Health Research

Reproductive health research in CDRI focuses on female and male contraceptives, spermicides with anti-STI properties, agents for the management of osteoporosis, cancer breast and benign prostatic hyperplasia.

 

Global population is projected to rise exponentially from the current ~6 billion to 9 billion in 2050. Indian population, which contributes to one sixth of present world population, is expected to touch 1264 million in 2016. According to the World Health Organization, the family planning needs of more than 120 million couples goes unmet every year resulting in an annual abortion rate of 46 million. Most of these abortions take place in developing countries under unsafe and insanitary conditions causing the death of 68000 women per year. The Ministry of Health and Family Welfare, Government of India is supporting a long-term innovative Reproductive Health Research Program with focus on contraceptive development at the Central Drug Research Institute, Lucknow. In addition, given increased longevity, particularly among women, postmenopausal disorders including osteoporsis and breast cancers occur more frequently. The overall objectives of the program are to design and synthesize novel molecules/isolate from natural sources and bioevaluate them for generating new leads and to develop them as female or male contraceptives, spermicides with anti-STI properties, agents for the management of osteoporosis, breast cancer and benign prostatic hyperplasia, evaluate traditional remedies for fertility regulation and endocrine disorders, understand mode of action of promising agents and undertake basic research to generate new knowledge on male and female reproductive endocrinology relevant to fertility regulation and endocrine disorders.

 

 
BASIC RESEARCH
Objective: To generate new knowledge on male and female reproductive endocrinology relevant to fertility regulation and endocrine disorders due to menopause and andropause.
 
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Novel antispermatogenic compounds targeting Sertoli cell functions, male germ cell tight junctions and study of ubiquitin mediated protein degradation pathway in male contraception
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Studies on male infertility – protective effect of shilajit against cadmium induced infertility in male mice.

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To develop osteogenic (bone forming) molecules and preparations.

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Studies on antiproliferative action of   2,3-diaryl-2H-1- benzopyran derivative  in human endometrial cancer cells (Ishikawa cells) and human BPH-derived prostatic stromal cells.

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Naturally-derived naphthaquinone compounds induce apoptosis of prostate and endometrial cancer cells: mechanism of action studies; novel SERMs for management of BPH.
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 Triaryl pyranones as a potential new class of anti-breast cancer agents
 
DRUG DESIGN AND SYNTHESIS
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Synthetic chalcone-based beta adrenergic receptor modulators to elicit transient PTH stimulation as a way to enhance osteoblast function.
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Following leads from some natural compounds to stimulate bone morphogenic proteins production by osteoblasts, benzofurochomenes are being developed as rapid fracture healing agents.

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A newly discovered novel compound, dihydroflavone glycoside, from terrestrial plant source as bone anabolic agent for the treatment of postmenopausal osteoporosis.
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Disulfide esters of carbothioic acid, benzenepropanamine analogues and carbodithioic acid derivaties are being designed for selectively targeting sulfhydryl groups on human sperm surface that render membrane fluidity which is essential for motility and normal physiology.
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Imidazolophenoxyphenylpropyl amines are envisaged to introduce antimicrobial activity in spermicidal scaffolds for developing microbicidal contraceptives for vaginal use.
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Pyranoquinoline derivatives as novel agents for management of BPH through estrogen receptor mediated pathway.
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3,4,6-triaryl-2-pyranones and 2,3,4-triarylbenzopyran derivatives as a new class of therapeutic agent for breast cancer.
 
SCREENING AND DRUG DEVELOPMENT
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Design and synthesis of new and novel non-steroidal molecules for post-coital   contraceptive efficacy; collection and bioevaluation of medicinal plants for anti-implantation activity and follow-up studies on promising agents.
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Development   of   safe   and    effective contraceptives   that   exert action on testis (spermiogenesis), epididymis (sperm maturation/fertilization) or on sperm (spermicidal).
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Designing novel drugs and formulations for use as dual protection vaginal contraceptives for protection against unwanted pregnancy and STDs/STIs.

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Screening and development of natural and synthetic compounds having osteoblast promoting functions in vitro and bone anabolic effect in vivo.

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Developing agents exhibiting potent anti-proliferative activity, but being free from estrogen-related health hazards, for the management of breast cancer.

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Establishment of test systems for screening of synthetic compounds/natural products against BPH and mechanism of action studies with active agents on proliferative and apoptotic indices and other parameters in prostatic tissue.
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Developing agents for prevention of estrogen deficiency and age related bone loss, but lacking carcinogenic effect of estrogen on the endometrium and breast, in addition to being free from other estrogen-related health hazards
 
SIGNIFICANT ACHIEVEMENTS
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Centchroman*, the world's first non-steroidal weekly oral contraceptive.- Licensed to Industry

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Consap*, a herbal intravaginal contraceptive cream containing "Reetha" saponins as spermicide.- Licensed to Industry
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Isaptent, an aid for medical termination of pregnancy developed by utilizing "Isapgol" seed husk.

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Centchroman for the management of dysfunctional uterine bleeding.

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Compound  CDRI-99/373 (a new antiosteoporosis/anti-resorptive agent)

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Several other promising new drug candidates for osteoporosis (osteogenic agents) and vaginal contraception are under advanced stages of pre-clinical development.

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CDR-F147 (OsteoJuvenate) for optimal bone health as nutraceutical supplement - Licensed to Natural Remedies, Bengaluru
 
 
RECENT PUBLICATIONS
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 Sharan K, Swarnkar G, Siddiqui JA, Khan K, Kumari R, Rawat P, Maurya R, Sanyal S, Chattopadhyay N. A novel quercetin analog from a medicinal plant promotes peak bone mass achievement, bone healing after injury and exerts anabolic effect on osteoporotic bone: the role of aryl hydrocarbon receptor as a mediator of osteogenic action. J Bone Miner Res (in press), PMID: 21638315.
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 Lal N, Kumar L, Sarswat A, Jangir S, Sharma V L. Synthesis of S-(2-Thioxo-1,3-dithiolan-4-yl)methyl dialkylcarbamothioate and S-thiiran-2-ylmethyl dialkylcarbamothioate via intermolecular O−S rearrangement in water. Org Lett 13:2330–2333, 2011.
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 Dhar Dwivedi SK, Singh N, Kumari S, Mishra JS, Tripathi S, Banerjee P, Shah P, Kukshal V, Tyagi AM, Gaikwad AN, Chaturvedi RK, Mishra DP, Trivedi AK, Sanyal S, Chattopadhyay N, Ramachandran R, Siddiqui MI, Bandyopadhyay A, Arora A, Lundåsen T, Anak SP, Moore DD, Sanyal S. Bile acid receptor agonist GW4064 regulates PPARg coactivator-1a expression through estrogen receptor-related receptor a. Mol Endocrinol 25:922-32, 2011.
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 Siddiqui JA, Swarnkar A, Sharan K, Chakravarti B, Gautam AK, Rawat P, Kumar M, Gupta V, Manickavasagam L, Dwivedi AK, Maurya R, Chattopadhyay N. A naturally occurring rare analogue of quercetin promotes peak bone mass achievement and exerts anabolic effect on osteoporotic bone. Osteoporos Int (in press), PMID: 21225417.
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 Tyagi AM, Srivastava K, Kureel J, Kumar A, Raghuvanshi A, Yadav D, Maurya R, Goel A, Singh D. Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos Int (in press), PMID: 21562872.
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 Sarswat A, Kumar R, Kumar L, Lal N, Sharma S, Prabhakar YS, Pandey SK, Lal J, Verma V, Jain A, Maikhuri JP, Dalela D, Kirti, Gupta G, Sharma VL. Arylpiperazines for management of benign prostatic hyperplasia: design, synthesis, quantitative structure-activity relationships, and pharmacokinetic studies. J Med Chem54:302–311, 2011.
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 Pooja S, Francis A, Bid HK, Kumar S, Rajender S, Ramalingam K, Thangaraj K, Konwar R. Role of ethnic variations in TNF-α and TNF-β polymorphisms and risk of breast cancer in India. Breast Cancer Res Treat 126:739-47, 2011.
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 Rajender S, Francis A, Pooja S, Krupakar N, Surekha D, Reddy G, Rao DR, Rao L, Ramachandra S, Vishnupriya S, Ramalingam K, Satyamoorthy K, Thangaraj K. CAG repeat length polymorphism in the androgen receptor gene and breast cancer risk: data on Indian women and survey from the world. Breast Cancer Res Treat 127:751-60, 2011.
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 Pal P, Kanaujiya JK, Lochab S, Tripathi SB, Bhatt ML, Singh PK, Sanyal S, Trivedi AK. 2-D gel electrophoresis-based proteomic analysis reveals that ormeloxifen induces G0-G1 growth arrest and ERK-mediated apoptosis in chronic myeloid leukemia cells K562. Proteomics 11:1517-29, 2011.
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 Kumar A, Singh AK, Gautam AK, Chandra D, Singh D, Changkija B, Singh MP, Trivedi R. Identification of kaempferol-regulated proteins in rat calvarial osteoblasts during mineralization by proteomics. Proteomics 10:1730-9, 2010.
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 Dama MS, Singh NM, Rajender S. High fat diet prevents over-crowding induced decrease of sex ratio in mice. PLoS One 6:e16296, 2011.
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 Tyagi AM, Srivastava K, Sharan K, Yadav D, Maurya R, Singh D. Daidzein prevents the increase in CD4+CD28null T cells and B lymphopoesis in ovariectomized mice: a key mechanism for anti-osteoclastogenic effect. PLoS One (in Press).
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 Gautam AK, Bhargavan B, Tyagi AM, Srivastava K, Yadav DK, Kumar M, Akanksha, Mishra JS, Singh AB, Sanyal S, Maurya R, Mackivasagam L, Singh SP, Wahajuddin, Jain GK, Chattopadhyay N, Singh D. Differential effects of formononetin and cladrin on osteoblast function, peak bone mass achievement and bioavailability in rats. J Nutr Biochem 22:318-27, 2011.
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 Bhargavan B, Singh D, Gautam AK, Mishra JS, Kumar A, Goel A, Dixit M, Pandey R, Manickavasagam L, Dwivedi SD, Chakravarti B, Jain GK, Ramachandran R, Maurya R, Trivedi A, Chattopadhyay N, Sanyal S. Medicarpin, a legume phytoalexin, stimulates osteoblast differentiation and promotes peak bone mass achievement in rats: evidence for estrogen receptor b-mediated osteogenic action of medicarpin. J Nutr Biochem (in press), PMID: 21333515.
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 Kumar R, Verma V, Jain A, Jain RK, Maikhuri JP, Gupta G. Synergistic chemoprotective mechanisms of dietary phytoestrogens in a select combination against prostate cancer. J Nutr Biochem (in press), PMID: 21062672.
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 Kharkwal G, Fatima I, Kitchlu S,  Singh B, Hajela K, and Dwivedi A. Anti-implantation effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H benzo(b)pyran, a potent antiestrogenic agent in rats. Fertil Steril 95:1322-1327, 2011.
 
 
 
SCIENTISTS ASSOCIATED WITH THE PROJECT
Biology Chemistry
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 Dr. Naibedya Chattopadhyay
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 Dr Rakesh Maurya
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 Dr. (Mrs.) Anila Dwivedi
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 Dr (Ms.) Kanchan Hazela
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 Dr. Gopal Gupta
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 Dr V L Sharma
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 Dr. F W Bansode
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 Dr. Atul Kumar
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 Dr D P Mishra
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 Dr Atul Goel
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 Dr Rajender Singh
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 Dr R P Tripathi
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 Dr. (Mrs.) Divya Singh
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 Dr Gautam Panda
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 Dr (Mrs.) Ritu Trivedi
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 Dr Rituraj Konwar
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 Dr M Sachdev
Drug Delivery and Kinetics
• Dr S Sanyal
• Dr K R Arya • Dr A K Dwivedi
• Dr Anil Balapure • Dr Amit Misra
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 Dr Rajesh Jha
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 Dr Prabhat R Mishra
• Dr Syed Musthapa • Dr JR Gayen
    • Dr Wahajuddin
   
 
 
 
 
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