Phytoestrogens as inhibitors of fungal 17β-hydroxysteroid dehydrogenase

Different phytoestrogens were tested as inhibitors of 17 beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17 beta-HSDcl), a member of the short-chain dehydrogenase/reductase superfamily. Phytoestrogens inhibited the oxidation of 100 mu M 17 beta-hydroxyestra-4-en-3-one and the reduction of 100 mu M estra-4-en-3,17-dione, the best substrate pair known. The best inhibitors of oxidation, with IC50 below 1 mu M, were flavones hydroxylated at positions 3, 5 and 7: 3-hydroxyflavone, 3,7-dihydroxyflavone, 5,7-dihydroxyflavone (chrysin) and 5-hydroxyflavone, together with 5-methoxyflavone. The best inhibitors of reduction were less potent; 3-hydroxyflavone, 5methoxyflavone, coumestrol, 3,5,7,4'-tetrahydroxyflavone (kaempferol) and 5-hydroxyflavone, all had IC50 values between 1 and 5 mu M. Docking the representative inhibitors chrysin and kaempferol into the active site of 17 beta-HSDcl revealed the possible binding mode, in which they are sandwiched between the nicotinamide moiety and Tyr212. The structural features of phytoestrogens, inhibitors of both oxidation and reduction catalyzed by the fungal 17 beta-HSD, are similar to the reported structural features of phytoestrogen inhibitors of human 17 beta-HSD types 1 and 2. (c) 2005 Elsevier Inc. All rights reserved.