Several new coumarin and chromene prototype derivatives have been synthesised and evaluated for their ERa and ERb selective activity. Coumarin prototype compounds 18 & 19 were found to be ERa selective and the most active, exhibiting potential antiproliferative activity against both ER +ve & ER Àve breast cancer cell lines. The surprise finding of the series, however, are the novel prototype III chromenes 45 & 46, with aroyl substitution at the 6 th position. Both the compounds have shown potent antiproliferative activity against both the breast cancer cell lines, promote alkaline phosphatase activity, enhance osteoblast mineralization in vitro, significantly decrease ERE-ERa dependent transactivation and induce ERb activity. This specific upregulation of ERb isoform activity of compound 45 may be responsible for the antiosteoporotic activity at picomolar concentration. In addition, both the compounds were also devoid of any estrogenic activity, which correlates to their antiestrogenic behaviour in the two breast cancer cell lines. Assessment of selectivity using specific SiRNAs for ERa and ERb revealed that most of the compounds showed ERa and ERb-mediated action, except compound 28, which showed selectivity to ERa only. Computational docking analysis of active compounds 18 and 45 was conducted to correlate the interaction with the two receptors and it was found that the docked conformations of the coumarin prototype, compound 18 at ERa and ERb active sites were more or less superimposable on each other. However, the unique orientation of the aminoalkoxy side chain of novel chromene (prototype III) compound 45 in the ERb binding cavity may be responsible for its potential biological response.

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A library of 3,4,6‐triaryl‐2‐pyridones has been synthesized using multicomponent reaction (MCR) of substituted acetophenones, benzaldehydes and phenyl acetamides. All the synthesized compounds were evaluated for their anti‐breast cancer activity, in vitro in ER+ and ER‐ cancer cell lines, wherein, compounds 11 (4‐(3,4‐dimethoxyphenyl)‐6‐(4‐methoxyphenyl)‐3‐phenylpyridin‐2(1H)‐one) and 35 (3,6‐bis(4‐methoxyphenyl)‐4‐(4‐(2‐(piperidin‐1‐yl) ethoxy)phenyl)pyridin‐2(1H)‐one) were found to be the most active with best safety profile towards non‐cancer originated HEK‐293 cells. Cell cycle analysis showed that the compounds 11 and 35 induced statistically significant arrest of cells in G1 phase and reduction in S‐phase cells in a dose‐dependent manner. Compound 11, unlike compound 35 exerts breast cancer cell membrane specific action as observed with LDH assay, whereas compound 35 induced ROS‐independent mitochondrial‐mediated apoptosis in breast cancer cell line, MDA‐MB‐231. Apoptotic activity of compound 35 was also confirmed by DNA fragmentation and by expression of pro‐apoptotic genes, BAD, BAK, and BimL. Compound 35 is about five times safer than its effective IC50 values in MDA‐MB‐231 cell line, which makes it a non‐toxic breast cancer therapeutic agent.

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