Development of the -lactam type molecular scaffold for selective estrogen receptor modulator action: synthesis and cytotoxic effects in MCF-7 breast cancer cells

The estrogen receptors (ER and ER) which are ligand inducible nuclear receptors are recognized as pharmaceutical targets for diseases such as osteoporosis and breast cancer. There is an increasing interest in the discovery of subtype Selective Estrogen Receptor Modulators (SERMs). A series of novel -lactam compounds with estrogen receptor modulator properties have been synthesized. The antiproliferative effects of these compounds on human MCF-7 breast tumor cells are reported, together with binding affinity for the ER and ER receptors. The most potent compound 15g demonstrated antiproliferative effects on MCF-7 breast tumor cells (IC50=186nM) and ER binding (IC50=4.3nM) with 75-fold ER/ receptor binding selectivity. The effect of positioning of the characteristic amine containing substituted aryl ring (on C-4 or N-1 of the -lactam scaffold) on the antiproliferative activity and ER-binding properties of the -lactam compounds is rationalized in a molecular modeling study.