Chromene-3-carboxamide derivatives discovered from virtual screening as potent inhibitors of the tumour maker, AKR1B10

被引：65

作者：

Endo, Satoshi ^{[1
,3
]}

Matsunaga, Toshiyuki ^{[1
]}

Kuwata, Kazuo ^{[2
]}

Zhao, Hai-Tao ^{[4
]}

El-Kabbani, Ossama ^{[4
]}

Kitade, Yukio ^{[3
]}

Hara, Akira ^{[1
]}

机构：

[1] Gifu Pharmaceut Univ, Biochem Lab, Gifu 5011196, Japan

[2] Ctr Emerging Infect Dis, Grad Sch Med, Div Prion Res, Gifu 5011193, Japan

[3] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Gifu 5011193, Japan

[4] Monash Inst Pharmaceut Sci Med Chem & Drug Act, Parkville, Vic 3052, Australia

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 07期

基金：

日本学术振兴会;

关键词：

AKR1B10; Aldose reductase-like protein; Aldose reductase; Aldehyde reductase; Inhibition selectivity; Molecular docking; HUMAN ALDOSE REDUCTASE; COLORECTAL-CANCER CELLS; ALDEHYDE REDUCTASE; ACTIVE-SITE; PROTEIN; IDENTIFICATION; B10; OVEREXPRESSION; PURIFICATION; EXPRESSION;

D O I：

10.1016/j.bmc.2010.02.050

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A human aldose reductase-like protein, AKR1B10 in the aldo-keto reductase (AKR) superfamily, was recently identified as a therapeutic target in the treatment of several types of cancer. In order to identify potential leads for new inhibitors of AKR1B10, we adopted the virtual screening approach using the automated program ICM, which resulted in the discovery of several chromene-3-carboxamide derivatives as potent competitive inhibitors. The most potent (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide inhibited the reductase activity of AKR1B10 with a K-i value of 2.7 nM, and the metabolism of farnesal and 4-hydroxynonenal in the AKR1B10-overexpressed cells from 0.1 mu M with an IC50 value equal to 0.8 mu M. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2485 / 2490

页数：6

共 37 条

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