Anti-androgenic curcumin analogues as steroid 5-alpha reductase inhibitors

Anti-androgen can be used in the treatment of benign prostatic hyperplasia, acne, hirsutism, and androgenic alopecia. For the search of anti-androgenic activity through steroid 5-alpha reductase (S5 alpha R) inhibition mechanism, 12 natural analogs from plant origins, i.e., curcumin (1) demethoxycurcumin (2), and bisdemethoxycurcumin (3) isolated from Curcuma longa Linn., compounds 18, 20, 21, 22, 24, and 25 isolated from Curcuma comosa Roxb., amide analogs 29-31 obtained from Bougainvillea spectabilis Willd. together with 21 synthesized analogs were evaluated for S5 alpha R inhibitory activity using liquid chromatography-mass spectrometry assay. The results showed that compounds 1, 2, 4, 5, 6, 7, and 9 possessed S5 alpha R inhibitory activity and compounds 1, 4, and 5 were the most potent (IC50 of 13.4 +/- 0.4, 15.3 +/- 3.1 and 8.9 +/- 0.9 A mu M, respectively). This suggests that the unsaturated enone moiety in the chain linked between two aromatic rings of curcumin analog was imperative to the activity. Moreover, the m-methoxyl and p-hydroxyl substitutions in aromatic region of 1,6-heptadiene-3,5-dione linker were necessary. The cytotoxic effect on androgen-dependent cell, human dermal papilla was investigated to obtain safety information profile. We found that 1,6-heptadiene-3,5-dione linker was important for safety. This work stated that anti-androgen activity of curcumin analogs was through S5 alpha R inhibition mechanism and the information might lead to further design of new curcumin analogs with improved potency and safety.