DOCKING AND CYTOTOXICITY STUDIES OF 2-VINYLCHROMONE DERIVATIVES ON HUMAN BREAST CANCER CELL LINES
Keywords:Estrogen receptor, 2-vinylchromone, Docking, Anticancer, MCF-7, MDA-MB-231
Objective: Estrogen receptor (ER) is over-expressed in 70% of breast cancers. The ER has two isoforms, ERÎ± and ERÎ². The ER ligand binding domain (LBD) has been the target for hormone-responsive breast cancer. Due to tissue-specific effects currently available drugs for hormone positive breast cancer presents serious limitation. The dynamic and plastic nature of ER LBD plays a crucial role in ligand design that discriminates between the ER subtypes. Agents that selectively target ER isoform are a formidable challenge to researchers. The chromone scaffold is a privileged scaffold for exploration of anticancer agents. The objective of the present study was to evaluate the anticancer activity of a small library of 2-vinylchromones in human breast cancer cell lines MCF-7 and MDA-MB-231.
Methods: The compounds were synthesized by the reported procedures. Docking studies of the substituted 2-vinylchromone was performed using GLIDE tool in Maestro 8.0. The compounds were evaluated for anticancer activity against MCF-7 (ERÎ± positive), MDA-MB-231 (ERÎ² positive) and MRC-5 (ERÎ±, Î² negative) cell lines using MTT assay.
Results: The in silico studies indicated that substituted 2-vinylchromones, 1(a-c) and 2(a-b) exhibited comparable docking score at LBD of ERÎ± and ERÎ². However, the binding affinity of the compounds for the allosteric binding site in ERÎ² was negligible. The dose-dependent studies using MTT assay depicted that compounds 1(a-c) and 2(a-b) exhibited anticancer activity in ERÎ± positive cell line MCF-7 as compared to ERÎ² positive cell line MDA MB 231. The most potent anticancer activity was observed for compound 2b against MCF-7 cells with IC50 value of 15.625 Î¼g/ml.
Conclusion: The present investigation indicated that 2-vinylchromone derivatives exhibited ER isoform selectivity and the presence of bulky group in 2-vinylchromones resulted in significantly higher cytotoxicity in ERÎ± positive cell lines as compared to the ERÎ² positive cell line.
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