Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia.
Eur J Med Chem. 2013 Apr;62:89-97. doi: 10.1016/j.ejmech.2012.12.045. Epub 2013 Jan 3.
The aldo-keto reductase AKR1C3 is an important target for the development of new drugs. Selective inhibitors of this enzyme are needed because they should not inhibit other, structurally closely related AKR1C isoforms. A comprehensive series of 2,3-diarylpropenoic acids was synthesized and evaluated for the inhibition of AKR1C1-AKR1C3. We found that the 4-methylsulfonylphenyl substituent at position 2 of these acids is required to exhibit the selective inhibition of AKR1C3. The best results were obtained for the compounds that fulfill the above requirement and possess a 4-bromophenyl, 4-methylthiophenyl, 4-methylphenyl or 4-ethylphenyl substituent at position 3 of the substituted propenoic acids (i.e., acids 28, 29, 37, and 39, respectively). These compounds represent an important step toward the development of drug candidates for a treatment of the hormone-dependent and hormone-independent forms of prostate and breast cancers.
醛酮还原酶 1C3（aldo-keto reductase AKR1C3）是开发新药的重要靶点。因为这些酶抑制剂不应抑制其他结构上密切相关的 AKR1C 同工酶，所以需要选择性抑制剂。我们合成了一系列 2,3-二芳基丙烯酸，并对其抑制 AKR1C1-AKR1C3 的活性进行了评价。我们发现这些酸在 2 位的 4-甲磺酰基苯基取代基是表现出对 AKR1C3 选择性抑制所必需的。对于满足上述要求且在取代的丙烯酸的 3 位具有 4-溴苯基、4-甲基噻吩基、4-甲基苯基或 4-乙基苯基取代基的化合物（即酸 28、29、37 和 39），获得了最佳结果。这些化合物是开发用于治疗激素依赖性和激素非依赖性前列腺癌和乳腺癌候选药物的重要步骤。
