Bioorganic & Medicinal Chemistry 2010-01-01

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

Solomon Berhe, Andrew Slupe, Choice Luster, Henry A Charlier, Don L Warner, Leon H Zalkow, Edward M Burgess, Nkechi M Enwerem, Oladapo Bakare

Index: Bioorg. Med. Chem. 18(1) , 134-41, (2010)

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Abstract

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 IC(50) values ranging from 3-5 microM. 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 microM. 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.Copyright (c) 2009 Elsevier Ltd. All rights reserved.