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

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.

• Authors: Wei Zhang, Ling Wang, Liping Zhang, Wenli Chen, Xinying Chen, Minyu Xie, Guangmei Yan, Xiaopeng Hu, Jun Xu, Jingxia Zhang
• Journal: Steroids (Steroids) Vol. 86 Pg. 39-44 (Aug 2014) ISSN: 1878-5867 [Electronic] United States
• PMID: 24793566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Steroids
• AKR1B10 protein, human
• Aldo-Keto Reductases
• Aldehyde Reductase

Topics

• Aldehyde Reductase (antagonists & inhibitors, metabolism)
• Aldo-Keto Reductases
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Conformation
• Stereoisomerism
• Steroids (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship