Anti-estrogenic activity of mansonone G and mansorin A derivatives.

CONTEXT

Mansonone G and mansorin A are major bioactive constituents from Mansonia gagei Drumm (Sterculiaceae) wood, and their mild anti-estrogenic activity was reported previously by the authors.

OBJECTIVE

In order to increase the potency of their anti-estrogenic effect and to clarify their binding way to estrogen receptor on a molecular level, several derivatives of both compounds will be prepared and a docking study of the original compounds and their derivatives on estrogen receptor alpha (ERα) was carried out.

MATERIALS AND METHODS

The original compounds were isolated from the heartwood of M. gagei. Nine alkyl derivatives were prepared by acetylation, methylation, or adding a basic side chain to the free hydroxyl group of both compounds. The estrogenic/anti-estrogenic activities of the derivatives compared to the original compounds were carried out using ERα competitive binding screen and yeast two-hybrid assay expressing ERα and ERβ using concentrations ranging from 10 to 100 μM.

RESULTS

Acetyl mansonone G showed a 10-fold increase in its binding ability to ERα compared to mansonone G with an IC₅₀ 630 μM. Similarly, methyl mansonone G and acetyl mansonone G showed 50% and 35% inhibition of 17β-estradiol-induced β-galactosidase activity at 10 μM in the yeast expressing ERα, and 42% and 30%, respectively, at 10 μM in the yeast expressing ERβ. Virtual docking of acetyl mansonone G to ERα showed that it binds, with its acetyl oxygen, in a similar way to the 17β-OH of estradiol.

DISCUSSION AND CONCLUSION

The phenolic hydroxyl group in mansonones and mansorins was not essential for binding to estrogen receptors. In addition, acetyl mansonone G could represent a promising starting material for the synthesis of anti-estrogenic agents.