Design, synthesis and biological evaluation of novel indone derivatives as selective ERβ modulators

To reduce the endometrial toxicity and improve the efficacy of current selective estrogen receptor modulators used in breast cancer treatment by enhancing ERβ selectivity, inspired by active resveratrol oligomer, a series of analogs ( 5a–f , 6a–b , 7a–d , 8a–d ) were designed, synthesized and biologically evaluated. Among them, the chiral indone analog (2 R ,3 R ) -8a exhibited best antiproliferative activity against both breast cancer cell lines (MDA-MB-231 and MCF-7) and better safety profile on uterus than tamoxifen. Analog (2 R ,3 R ) -8a demonstrated good binding affinity and selectivity toward ERβ, which was further proved by both molecular docking and radiometric competitive binding assay. Other studies for (2 R ,3 R ) -8a also have been explored including cell cycle and apoptosis evaluation and in vitro metabolic stability studies. These results demonstrated that (2 R ,3 R ) -8a could be a promising lead compound for future exploration of selective ERβ anti-breast cancer agents.