Brozic Petra, Golob Barbara, Gomboc Natasa, Rizner Tea Lanisnik, Gobec Stanislav
Institute of Biochemistry, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia.
Mol Cell Endocrinol. 2006 Mar 27;248(1-2):233-5. doi: 10.1016/j.mce.2005.10.020. Epub 2005 Dec 6.
17Beta-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 AKR1C3. 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 microM). Also, unsubstituted cinnamic acid was a good inhibitor of AKR1C3 (IC50=50 microM). 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 AKR1C3.
17β-羟类固醇脱氢酶5型（AKR1C3）参与人体雄激素和雌激素作用的受体前调节，是治疗激素依赖性癌症（如前列腺癌、乳腺癌和子宫内膜癌）的一个新兴治疗靶点。为了发现新型抑制剂，我们测试了一系列肉桂酸对人重组AKR1C3还原活性的影响。使用9,10-菲醌作为底物，通过分光光度法对这些化合物进行评估。该系列中最佳抑制剂是α-甲基肉桂酸（IC50 = 6.4微摩尔）。此外，未取代的肉桂酸也是AKR1C3的良好抑制剂（IC50 = 50微摩尔）。苯环上的小疏水取代基不会改变活性；然而，用极性基团取代会降低抑制效力。该系列中活性最高的化合物是进一步进行结构修饰以寻找更有效AKR1C3抑制剂的有前景的起始点。
