S-fluorenylmethoxycarbonyl glutathione and diesters: inhibition of mammalian glyoxalase II.
Inhibitors having high specificity toward mammalian glyoxalase II, but not glyoxalase I, were sought as part of a program to study glyoxalase enzyme function in mammalian cells. The compound, S-fluorenylmethoxycarbonyl glutathione (FMOC-G), was synthesized and found to be a competitive inhibitor of purified calf liver glyoxalase II (Ki = 2.1 mumol/l). Inhibition constants (Ki values) for the other glyoxalase enzyme, glyoxalase I, and the glutathione-requiring enzyme, glutathione S-transferase, from other sources, were found to be 17 and 25 mumol/l, respectively. FMOC-G is a very poor inhibitor of glutathione reductase and glutathione peroxidase. Diesters (dimethyl, diethyl, diisopropyl) of FMCO-G were also synthesized, as proinhibitors, to improve transport of FMOC-G into mammalian tumor cells (rat adrenal pheochromocytoma, PC-12) in culture. The diesters were inhibitory to cell growth and variability; the most effective of these, diisopropyl FMOC-G, exhibited an [I]0.5 value of approximately 275 mumol/l. Diesters of FMOC-G may be useful in studies of the glyoxalase enzyme system in cultured mammalian cells.
Chyan
M K
MK
Department of Biology, University of North Texas, Denton, USA.
Elia
A C
AC
Principato
G B
GB
Giovannini
E
E
Rosi
G
G
Norton
S J
SJ
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004952:Esters; D005449:Fluorenes / Q000138:chemical synthesis / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007700:Kinetics; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D016716:PC12 Cells; D051381:Rats; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099301:Hydroxyacylglutathione Hydrolase
D004791:Enzyme Inhibitors; D004952:Esters; D005449:Fluorenes; D005978:Glutathione; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D007791:Lactoylglutathione Lyase; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase; C098261:S-fluorenylmethoxycarbonylglutathione