S-(N-aryl-N-hydroxycarbamoyl)glutathione derivatives are tight-binding inhibitors of glyoxalase I and slow substrates for glyoxalase II.
S-(N-Aryl-N-hydroxycarbamoyl)glutathione derivatives are powerful competitive inhibitors of the anticancer target enzyme glyoxalase I. Indeed, the N-p-bromophenyl derivative is the strongest inhibitor of the enzyme from human erythrocytes yet reported (Ki = 1.4 x 10(-8) M). Structure-activity correlations indicate that the high affinities of the derivatives for both human and yeast glyoxalase I are due to the fact that the derivatives are hydrophobic analogs of the enediol(ate) intermediate associated with the glyoxalase I reaction. The derivatives also proved to be slow substrates for the thioester hydrolase glyoxalase II (bovine liver). Compounds of this type are of interest as potential tumor-selective anticancer agents, based on the abnormally low levels of glyoxalase II activity in some types of cancer cells.
Murthy
N S
NS
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County 21228.
Bakeris
T
T
Kavarana
M J
MJ
Hamilton
D S
DS
Lan
Y
Y
Creighton
D J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D005978:Glutathione / Q000031:analogs & derivatives*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013869:Thiolester Hydrolases / Q000378:metabolism*; D000099301:Hydroxyacylglutathione Hydrolase
D000970:Antineoplastic Agents; D005978:Glutathione; D007791:Lactoylglutathione Lyase; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase