甾体衍生物作为AKR1B10选择性抑制剂的合成及生物学评价

Synthesis and biological evaluation of steroidal derivatives as selective inhibitors of AKR1B10.

作者信息

Zhang Wei, Wang Ling, Zhang Liping, Chen Wenli, Chen Xinying, Xie Minyu, Yan Guangmei, Hu Xiaopeng, Xu Jun, Zhang Jingxia

机构信息

School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou 510006, PR China.

Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, PR China.

出版信息

Steroids. 2014 Aug;86:39-44. doi: 10.1016/j.steroids.2014.04.010. Epub 2014 Apr 30.

DOI:10.1016/j.steroids.2014.04.010

PMID:24793566

Abstract

AKR1B10 is a member of human aldo-keto reductase superfamily, and a promising anti-cancer therapeutic target. In this paper, androst-5-ene-3β-ol, dehydroepiandrosterone, pregnenolone and cholesterol were used as reactants, sixteen products were obtained through Jones reaction and reduction reaction using NaBH4. Their inhibitory activities against AKR1B10 and AKR1B1 were measured. The most active compound (3a) has the IC50 of 0.50μM for AKR1B10, and the most AKR1B10 selective compound (2a) has the IC50 of 0.81μM with AKR1B1/AKR1B10 selectivity of 195. In addition, the binding modes of 2a and 3a in the active site of human AKR1B10 were identified by docking.

摘要

AKR1B10是人类醛酮还原酶超家族的成员，也是一个很有前景的抗癌治疗靶点。在本文中，以雄甾-5-烯-3β-醇、脱氢表雄酮、孕烯醇酮和胆固醇作为反应物，通过琼斯反应和使用硼氢化钠的还原反应得到了16种产物。测定了它们对AKR1B10和AKR1B1的抑制活性。活性最高的化合物（3a）对AKR1B10的IC50为0.50μM，对AKR1B10选择性最高的化合物（2a）的IC50为0.81μM，AKR1B1/AKR1B10选择性为195。此外，通过对接确定了2a和3a在人AKR1B10活性位点的结合模式。