Abstract
The design and synthesis of a library of natural product inspired benzocoumarin-chalcones chimeras, as potent and selective, novel, anti-breast cancer scaffold, is reported herein. Twenty-one new chimeric molecules, 25-45, were synthesized through an efficient protocol involving the Horner-Wadsworth-Emmons-olefination of beta-aryl-beta-ketophosphonates with 4-formyl-2H-benzo[h]chromen-2-ones as the key step, and evaluated for anti-proliferative activity against a panel of four breast cancer and related cell lines viz. MDA-MB-231 (ER-ve), MCF-7 (ER+ve), Ishikawa (endometrial cancer) and Hela (cervical cancer). The synthesized molecules showed in vitro anti-proliferative activity in a range of 7.42 to 74.68 mu M (IC50). Compounds 33 and 34 showed very good activity, with 34 exhibiting better activity than the standard drugs, tamoxifen and raloxifene. Interestingly, none of the compounds showed cytotoxity against the normal human cell line. To identify the possible targets of the active compounds, molecular docking analysis was conducted to correlate their interaction with the ER alpha and ER beta receptors. From among the active compounds the docked conformations of 34, at the ER alpha and ER beta active sites, showed that it fits most favorably in the ligand binding space and shows hydrophobic interactions with the salient residues. Based on the above findings, 34 was identified as a lead molecule for development of more potent anti-breast cancer agents.