Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase.
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.
Berhe
Solomon
S
Department of Chemistry, Howard University, Washington, DC 20059, USA.
Slupe
Andrew
A
Luster
Choice
C
Charlier
Henry A
HA
Warner
Don L
DL
Zalkow
Leon H
LH
Burgess
Edward M
EM
Enwerem
Nkechi M
NM
Bakare
Oladapo
O
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
D007191:Indazoles; D000429:Alcohol Oxidoreductases