Germacrene Analogs are Anti-androgenic on Androgen-dependent Cells

Abstract

Anti-androgenic drugs are treatments for androgen-related disorders such as benign prostatic hyperplasia, acne, hirsutism, and androgenic alopecia. Germacrone (1), a sesquiterpene isolated from hexane extracts of Curcuma aeruginosa Roxb. rhizome, is an androgen inhibitor of steroid 5-alpha reductase in-vitro. Here, we used the similarity of germacrone's α,ß-unsaturated carbonyl to testosterone's α,ß-unsaturated carbonyl to find germacrene analogs obtained from this plant and by semi-synthesis that might be more potent steroid 5-alpha reductase inhibitors. 8-Hydroxy germacrene B (4) was ~13-fold more potent than its parent, 1 and the most potent (IC₅₀, 0.15±0.022 mM) among 9 compounds tested. The conformation of its cyclodecadiene ring and the α,ß-unsaturated ketone/hydroxy in the germacrene molecule might be crucial role for its anti-androgen activity. Moreover, 1 and 4 showed mild cytotoxic effect on prostate cancer cells. Neither compound was cytotoxic towards human dermal papilla cells at 100 μg/mL. We show that this SAR strategy created promising anti-androgenics for androgen dependent disorders and may create further analogues with further improvements in selectivity and clinical efficacy.