Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase

被引：22

作者：

Berhe, Solomon ^{[1
]}

Slupe, Andrew ^{[2
]}

Luster, Choice ^{[2
]}

Charlier, Henry A., Jr. ^{[2
]}

Warner, Don L. ^{[2
]}

Zalkow, Leon H. ^{[3
]}

Burgess, Edward M. ^{[3
]}

Enwerem, Nkechi M. ^{[1
]}

Bakare, Oladapo ^{[1
]}

机构：

[1] Howard Univ, Dept Chem, Washington, DC 20059 USA

[2] Boise State Univ, Dept Chem & Biochem, Boise, ID 83725 USA

[3] Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 01期

基金：

美国国家科学基金会;

关键词：

Carbonyl reductase; Indazole-dione; Pyrazoloquinone; Anthracycline therapy; ANTHRACYCLINE CARDIOTOXICITY; CYTOSOLIC FRACTIONS; DOXORUBICIN; IRON; DAUNORUBICIN; METABOLITE; PURIFICATION; RAT;

D O I：

10.1016/j.bmc.2009.11.011

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 series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl reductase with a wide range of catalytic efficiencies, while four analogs display inhibitory activities with IC50 values ranging from 3-5 mu M. Two of the inhibitors were studied in greater detail and were found to be noncompetitive inhibitors against both NADPH and menadione with K-I values ranging between 2 and 11 mu M. Computational studies suggest that conformation of the compounds may determine whether the indazole-diones bind productively to yield product or nonproductively to inhibit the enzyme. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：134 / 141

页数：8

共 34 条

[1] Development of daunorubicin resistance in tumour cells by induction of carbonyl reduction [J].