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 glyoxalas e enzyme function in mammalian cells. The compound, S-fluorenylmethoxy carbonyl glutathione (FMOC-G), was synthesized and found to be a compe titive inhibitor of purified calf liver glyoxalase II (K-i = 2.1 mu mo l/l). Inhibition constants (K-i values) for the other glyoxalase enzym e, glyoxalase I, and the glutathione-requiring enzyme, glutathione S-t ransferase, from other sources, were found to be 17 and 25 mu mol/l, r espectively. 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 transpor t of FMOC-G into mammalian tumor cells (rat adrenal pheochromocytoma, PC-12) in culture. The diesters were inhibitory to cell growth and var iability; the most effective of these, diisopropyl FMOC-G, exhibited a n [I](0.5) value of approximately 275 mu mol/l. Diesters of FMOC-G may be useful in studies of the glyoxalase enzyme system in cultured mamm alian cells.