Selenium analogues of rintodestrant (G1T48) as potent estrogen receptor modulators and downregulators

Abstract

Targeted therapy is one of the modern directions in the fight against cancer. Nowadays, selective estrogen receptor modulators (SERMs) and downregulators (SERDs) are used as the first-line medical treatment for estrogen receptor positive (ER+) tumors. Herein we report the design and synthesis of 7 novel benzoselenophenes, and their ER-α binding activity and cytotoxicity. The TR-FRET competitive ER-α binding experiments have shown that (E)-3-(4-((6-hydroxy-2-(4-hydroxybenzoyl)benzo[b]selenophen-3-yl)oxy)phenyl)acrylic acid (21b) is a considerably more effective ER-α binder (IC₅₀ = 0.44 nM) than the widely known SERM drug raloxifene (IC₅₀ = 1.78 nM). Furthermore, 21b and other obtained selenium analogues are not toxic in rat cardiomyoblasts (H9C2), indicating that the substituted benzo[b]selenophene is a prospective scaffold for the development of ER-α modulators and downregulators for the treatment of ER+ cancers.