Genistein derivatives as selective estrogen receptor modulators: Sonochemical synthesis and in vivo anti-osteoporotic action

Abstract

Genistein derivatives were synthesized from genistein through a facile sonochemical approach in high yields. The bioassay was performed on ovariectomized (OVX) rats in terms of bone mineral density (BMD) and the weight of bone ash (WBA) to lead to the discovery of eight novel genistein-based selective estrogen receptor modulators. Attention to the structure–activity relationship disclosed that the newly introduced 2-hydroxyethylthio scaffolds were essential for the anti-osteoporotic activity. Moreover, the anti-osteoporotic action of genistein, deprivable by methylation, could be restored and enhanced by subsequent sulfonation. The most promising compound was 4′,5,7-tri[3-(2-hydroxyethylthio)propoxy]isoflavone, displaying 24% (or 8%) increment in BMD and 31% (or 11%) increase in WBA of the femora relative to those discerned with the OVX (or genistein) group. Acute toxicity test showed that none of the active compounds was acutely toxic.