Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

Abstract

Abstract Objectives Tamoxifen is the most commonly used selective estrogen receptor modulators (SERMs); however, patients often develop the acquired drug resistance on tamoxifen therapy. The aim of this study was to develop new SERMs. Methods Several novel cyclopropyl derivatives were designed and synthesized. The binding affinities of these compounds as well as the selectivity on subtype of estrogen receptor (ER) were assessed by fluorescence polarization. The antagonistic activity was also evaluated by dual-luciferase reporter assay. Key findings Our data identified five compounds (9a, 9b, 9d, 9e and 9f) with a higher selectivity on ERα than ERβ subtype, warranting further development as a subtype-selective ER modulator. The study of antiestrogen activity also demonstrated that compounds 9a, 9c-f acted as full functional antagonists for ERα. These compounds had no or very low cytotoxicity. Conclusions Although these cyclopropyl derivatives showed lower binding affinities on ERs compared to 17β-estradiol, five of these compounds exhibited binding to ERα only and therefore might serve as a promising lead compound for further development of novel subtype-selective SERMs.