title: Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase.
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.
authors: Department of Chemistry, Howard University, Washington, DC 20059, USA.
authors: Solomon
authors: S
authors: Berhe
authors: Andrew
authors: A
authors: Slupe
authors: Choice
authors: C
authors: Luster
authors: Henry A
authors: HA
authors: Charlier
authors: Don L
authors: DL
authors: Warner
authors: Leon H
authors: LH
authors: Zalkow
authors: Edward M
authors: EM
authors: Burgess
authors: Nkechi M
authors: NM
authors: Enwerem
authors: Oladapo
authors: O
authors: Bakare
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D000429:Alcohol Oxidoreductases