Govind Keshri

Pregnancy interceptive activity of Melia azedarach Linn. in adult female Sprague-Dawley rats

Ethanolic extract of the root of Melia azedarach Linn. (family: Meliaceae) collected from the Institute campus intercepted pregnancy in 60% and 75% adult female rats when administered at 250 and 500 mg/kg daily doses, respectively, on Days 1-10 post-coitum by the oral route. On fractionation, the activity was localized in the chloroform fraction of the ethanolic extract, which showed 80-100% activity at 250 mg/kg daily dose in repeat tests. In animals that became pregnant, there was also a significant reduction in mean number of implantations and all the implantations exhibited signs of resorption. Of the four major compounds isolated in sufficient quantity and characterized from the active chloroform fraction, two compounds showed only marginal (50%) contragestational effect. Further exploration of the active chloroform fraction, which is also devoid of estrogen agonistic activity at the contraceptive dose in immature rat bioassay, is being undertaken to identify and characterize the active principle(s).

Postcoital contraceptive activity of some indigenous plants in rats

Crude ethanolic extract of seeds of Cichorium intybus and aerial parts of Guetterda andamanica, Memcylon lushingtonii, and Solanum crassypetalum and their fractions were evaluated for postcoital contraceptive efficacy in adult female Sprague-Dawley rats. The extracts were administered orally in days 1-10 postcoitum, and significant contraceptive activity was observed. On fractionation, the activity was localized primarily in the chloroform- or butanol-insoluble fractions. The activity in these fractions was invariably associated with a significantly reduced number of implantations.

Postcoital interceptive activity of Wrightia tinctoria in Sprague-Dawley rats: a preliminary study.

BACKGROUND This study was aimed to investigate the pregnancy-interceptive activity of the stem bark of Wrightia tinctoria R.Br. (Family Apocynaceae) administered during the preimplantation, peri-implantation and early postimplantation periods by oral route in adult female Sprague-Dawley rats. STUDY DESIGN The ethanolic extract of the stem bark and its serial fractions were administered to female rats on Days 1-7 or 1-5 postcoitum (Day 1: day of sperm-positive vaginal smear) by the oral route. At autopsy on Day 10 postcoitum, the number and status of corpora lutea and implantations were recorded. For estrogen-agonistic activity, immature rats ovariectomized 7 days earlier received the test extract or the vehicle once daily for 3 days and, at autopsy on Day 4, uterine weight, status of vaginal opening and extent of vaginal cornification were recorded. RESULTS The ethanolic extract of the stem bark of W. tinctoria R.Br. inhibited pregnancy in 100% of rats when administered orally at a 250-mg/kg dose on Days 1-7 or 1-5 postcoitum. On fractionation, the hexane-soluble, chloroform-soluble, water-soluble and water-insoluble fractions showed 100% anti-implantation effect, while n-butanol-soluble fraction intercepted pregnancy in 75% of animals when administered in the Days 1-5 postcoitum schedule. In immature rat bioassay, the active ethanolic extract and its fractions exhibited moderate to potent estrogen-agonistic activity, which might be responsible for their contraceptive action in this species. CONCLUSIONS Findings demonstrate the antifertility activity of the ethanolic extract of the stem bark of W. tinctoria and its hexane-soluble, chloroform-soluble, water-soluble and water-insoluble fractions. Studies that pursue promising natural products (to identify contraceptive agents from natural sources lacking potent estrogenic activity) towards a fruitful conclusion for development/lead generation should continue.

Amide Derivatives of 2,3-diarylacrylophenone as Estrogen Receptor Binding Ligands

Substituted amidoalkyl derivatives of 2,3-diarylacrylophenones carrying the amide chain on the 3-aryl residue have been prepared by reacting corresponding phenolic 2,3-diarylacrylophenones with haloalkyl carboxylic acid esters, their hydrolysis and subsequent treatment with different alkyl amines. Compounds thus prepared were evaluated for their relative binding affinity (RBA) towards estrogen receptors (ER), estrogen agonistic and antagonistic activities. Out of eleven amide derivatives thus prepared, compounds 7, 13, 15-19, 23, 24 showed significant estrogen antagonistic activity. Interestingly the phenolic compound 7 and the acid ester 18 also exhibited estrogen inhibiting property. Majority of the dimethoxy derivatives (R = OCH(3)) showed significantly high estrogenic activity. In order to throw light on their SAR, In silico docking of the acrylophenone derivatives in the ligand binding site of the ERalpha and their comparison with pure steroidal estrogen antagonist ICI-164,384 and the non-steroidal antiestrogen raloxifene, was carried out. Crystal structure of compound 6 revealed relative trans-geometry of the 2(B) and 3(C) phenyl rings.

Synthesis of 3-phenyl-4-phenylvinyl Benzopyranones and the Corresponding 2,2-dimethyl-benzopyrans with Structural Similarity to Estradiol, as Estrogen Receptor Ligands

7-Methoxy-3-phenyl-4-phenylvinyl benzopyran-2-ones and the corresponding 2,2-dimethyl-benzopyrans, substituted with different alkylamino residues were synthesized. Except compound 13e, all compounds showed high level of estrogen agonistic activity (>81 %) whereas, compounds 13 b-e and 15a showed significant estrogen antagonistic activity (>20 %). X-Ray analysis of a 7-methoxy-3-phenyl-4-phenylvinyl benzopyran-2-one derivative 13d showed its structural resemblance to endogenous estrogen, 17beta-estradiol. Estrogenic and antiestrogenic activities of these derivatives demonstrate their estrogen receptor (ER) binding ability. The lack of hydroxyl groups at appropriate positions resulted in poor Relative Binding Affinity (RBA).

Evaluation of In-Vivo Anti-Implantation and In-Vitro Anti-Proliferative Activities of Substituted 3-phenyl-4-phenylvinyl Benzopyranone Derivatives

A series of substituted 3-phenyl-4-phenylvinyl benzopyranone derivatives (11a-e) was evaluated for their anti- implantation activity in mature female Sprague-Dawley rat model. Compounds were further evaluated for anti- proliferative activity in human adenocarcenoma breast cancer cell line (MCF-7 cancer cell line). The tested compounds showed significant anti-proliferative activity with moderate anti-implantation activity. The inhibitory concentration (IC50) values of most active compounds 11 (c-e) are 8.43 � M, 7.97 � M and 7.91 � M respectively and comparable to that of ta- moxifen (5.10 � M), a well known antiestrogen used for treatment of breast cancer.