46 Letters in Drug Design & Discovery, 2009, 6, 46-50 1570-1808/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Evaluation of In-Vivo Anti-Implantation and In-Vitro Anti-Proliferative Activities of Substituted 3-phenyl-4-phenylvinyl Benzopyranone Deriva- tives Atul Gupta* ,a , Ramesh Sharma c , Anil Kumar Balapure c , Govind Keshri b , M.M. Singh b and Suprabhat Ray a a Medicinal and Process Chemistry Division, b Tissue Culture and Animal Laboratory , c Endocrinology Division, Central Drug Research Institute, Lucknow-226001, India Received July 28, 2008: Revised October 22, 2008: Accepted October 24, 2008 Abstract: 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 (IC 50 ) 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. Keywords: Anti-implantation agents, Estrogen receptors, Estrogen agonists, Estrogen antagonists, Fertility regulation, Anti- proliferative agents, Drug Research. 1. INTRODUCTION Selective estrogen receptor modulators (SERMs), a class of pharmaceuticals, are important for the treatment of estro- gen dependent disorders due to their tissue selective action [1-4]. The tissue selectivity of a ligand lies in the ligand- receptor interactions which ultimately depend upon the stereochemistry of the molecule [5]. The ligand-receptor interactions are the outcome of structural complementarities of the ligand with ligand binding pocket of the estrogen re- ceptor (ER). Estrogen receptors (ER) are ligand inducible transcription factors that belong to nuclear receptor super family [6, 7]. Two subtypes of the estrogen receptor, ER- and ER- are known [8]. The ligand binding domain of the ER- and ER- are about 58% homologous. Irrespective to their subtype selectivity, all estrogen receptor ligands inter- act with both ER- and ER- up to certain extent [9]. Several nonsteroidal molecules have been investigated so far as es- trogen receptor ligands some of them are either in the market as drug or in the advanced phase of clinical studies. Briefly these compounds belong to the different chemical classes such as triarylethylene (TEA), benzothiaphenes, indoles and benzopyarans [10]. Beside their multifunctional use in treatment of different estrogen dependent disorders including breast cancer and osteoporosis, SERMs which possess tissue selective estrogen agonistic and antagonistic activities could also find their use in fertility regulation [10]. In reproductive cycle, suppression of secondary elevation in estrogen concentration, mainly of estradiol 1, by use of estrogen antagonists brings failure of ovum implantation (Fig. 1) [11]. Estrogen antagonistic *Address correspondence to this author at the Medicinal and Process Chem- istry Division, Central Drug Research Institute, Lucknow-226001, India; E-mail: atisky2001@yahoo.co.in Present Address: Département de Chimie-Biologie, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada G9A 5H7. action at this stage is apparently devoid of any side effects such as weight gain, pigmentation, breast tenderness and nausea which are generally associated with steroidal contra- ceptives [12-15]. In earlier search for estrogen receptor modulators at Cen- tral Drug Research Institute, India, introduction of ben- zopyran based SERM Ormeloxifene 2, the world’s first and only nonsteroidal oral contraceptive was made by our group [16]. Ormeloxifene 2, a 3,4-diaryl benzopyran derivative is a recemate and is marketed under the trade name of Saheli. Its other analogues as antiostioporotic and breast cancer agents are under advanced studies [17]. In order to explore the impact of structural modificaltions on biological activity, we have recently reported substituted 7-methoxy-3-phenyl-4-phenylvinyl benzopyran-2-one and 2,2-dimethyl 7-methoxy-3-phenyl-4-phenylvinyl benzopyran derivatives of type 3 and 4 as estrogen receptor ligands (Fig. 1) [18]. These novel compounds showed interesting estrogen agonistic and antagonistic activities. However, ben- zopyranone derivatives of type 3 possessed superior estrogen agonistic and antagonistic activities compared with the cor- responding benzopyrane derivatives. The significant and balanced estrogen agonistic and antagonistic activities of these benzopyranone derivatives of type 3 prompted us to further evaluate their potential as estrogen receptor modula- tors for their possible use in fertility regulation and treatment of other estrogen dependent disorders such as breast cancer, osteoporosis etc. This study presents in-vivo anti- implantation and in-vitro anti-proliferative activities results of these benzopyranone derivatives. 2. MATERIALS AND METHOD 2.1. Chemistry The target alkylamino substituted 7-methoxy-3-phenyl-4- phenylvinyl benzopyranone derivatives of type 3 were pre-