Synthesis of 3-[(N-Carboalkoxy)ethylamino]-Indazole-Dione Derivatives and Their Biological Activities on Human Liver Carbonyl Reductase

Authors

Solomon Berhe, Howard University
Andrew Slupe, Boise State University
Choice Luster, Boise State University
Henry A. Charlier, Boise State UniversityFollow
Don L. Warner, Boise State UniversityFollow
Leon H. Zalkow, Georgia Institute of Technology
Edward M. Burgess, Georgia Institute of Technology
Nkechi M. Enwerem, Howard University
Oladapo Bakare, Howard University

Document Type

Article

Publication Date

1-1-2010

DOI

http://dx.doi.org/10.1016/j.bmc.2009.11.011

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 IC₅₀ values ranging from 3–5 μM. 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 μM. 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.

Publication Information

Berhe, Solomon; Slupe, Andrew; Luster, Choice; Charlier, Henry A.; Warner, Don L.; Zalkow, Leon H.; Burgess, Edward M.; Enwerem, Nkechi M.; and Bakare, Oladapo. (2010). "Synthesis of 3-[(N-Carboalkoxy)ethylamino]-Indazole-Dione Derivatives and Their Biological Activities on Human Liver Carbonyl Reductase". Bioorganic & Medicinal Chemistry, 18(1), 134-141.