Cinnamic acids as new inhibitors of 17β-hydroxy steroid dehydrogenase type 5 (AKR1C3)

17 beta-Hydroxysteroid dehydrogenase type 5 (AKR1C3) that is involved in the pre-receptor regulation of androgen and estrogen action in the human is an emerging therapeutic target in the treatment of hormone-dependent forms of cancer, such as prostate cancer, breast cancer and endometrial cancer. To discover novel inhibitors, we tested the effect of a series of cinnamic acids on the reductive activity of the human recombinant AKRlC3. The compounds were evaluated in a spectrophotometric assay using 9,10-phenanthrenequinone as a substrate. The best inhibitor in the series was alpha-methylcinnamic acid (IC50 = 6.4 mu M). Also, unsubstituted cinnamic acid was a good inhibitor of AKRIC3 (IC50 = 50 mu M). Small hydrophobic substituents of the phenyl ring did not alter the activity; however, substitution with polar groups decreased the potency of inhibition. The most active compounds in this series represent promising starting points for further structural modifications in the search for more potent inhibitors of AKRlC3. (c) 2005 Elsevier Ireland Ltd. All rights reserved.