Estrogenic properties of prenylated isoflavones in U2OS human osteosarcoma cells: structure-activity relationships

In a continuation study aiming to discover novel phytoestrogens, we recently reported the isolation and characterization of novel and known isoflavonoids from Erythrina poeppigiana (Walp.) O.F. Cook. (Fabaceae), among which eight appear to be structurally related to genistein with isoprenyl and/or 7-methoxy substitution. In addition, significant binding affinities for the two isotypes of the estrogen receptor ERα and ERβ were demonstrated [1]. These isoflavones derivatives have been investigated for their estrogenic properties in receptor subtype specific reporter gene assay, with a particular focus on their estrogen receptor alpha and beta (ERα and ERβ) selectivity, and their structure-activity relationships using a bone-derived human osteosarcoma cell line (U2OS cells) stably expressing ERα or transiently expressing ERβ. According to our results, an isoprenyl substitution at position 3? together with a 7-methoxy substitution on the genistein skeleton is associated with a statiscally significant activation of the ERα- and ERβ-dependent reporter gene expression in U2OS cells starting from 0.1 nM; while for genistein itself a statistically significant activation was observable at 1 nM. On the other hand, a double prenylation at position 8 and 3? is associated with an almost complete loss of function on the reporter gene activation in U2OS-ERα, but in ERβ expressing system, the effectiveness remains on a statistically significant level, demonstrating an „exclusive ERβ-selectivity“ in U2OS human osteosarcoma cells.

References: 1. Djiogue, S. et al. (2009)J. Nat. Prod. 72 (9): 1603–1607.