A new method for rapidly generating inhibitors of glyoxalase I inside tumor cells using S-(N-aryl-N-hydroxycarbamoyl)ethylsulfoxides.

Abstract

The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione is a powerful mechanism-based competitive inhibitor of the anticancer target enzyme glyoxalase I. Nevertheless, this compound exhibits limited toxicity toward tumor cells in vitro because it does not readily diffuse across cell membranes. We describe an efficient method for indirectly delivering the enzyme inhibitor into murine leukemia L1210 cells via acyl interchange between intracellular glutathione and the cell-permeable prodrug S-(N-p-chlorophenyl-N-hydroxycarbamoyl)ethylsulfoxide. The second-order rate constant for the acyl-interchange reaction in a cell-free system is 1.84 mM-1 min-1 (100 mM potassium phosphate buffer, 5% ethanol, pH 7.5, 25 degrees C). Incubation of L1210 cells with the sulfoxide in vitro results in a rapid increase in the intracellular concentration of the glyoxalase I inhibitor (kapp = 1. 41 +/- 0.03 min-1 (37 degrees C)) and inhibition of cell growth (GI50 = 0.5 +/- 0.1 microM). This represents an improvement in both efficiency and potency over the dialkyl ester prodrug strategy in which the inhibitor is indirectly delivered into tumor cells as the [glycyl,glutamyl] diethyl or dicyclopentyl esters. The fact that pi-glutathione transferase catalyzes the acyl-interchange reaction between GSH and the sulfoxide suggests that the sulfoxide, or related compounds, might exhibit greater selective toxicity toward tumor cells that overexpress the transferase.

• Authors: D S Hamilton, M J Kavarana, E M Sharkey, J L Eiseman, D J Creighton
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 42 Issue 10 Pg. 1823-7 (May 20 1999) ISSN: 0022-2623 [Print] United States
• PMID: 10346934 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Prodrugs
• S-(N-4-chlorophenyl-N--hydroxycarbamoyl)glutathione dicyclopentyl ester
• S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione
• Glutathione Transferase
• Lactoylglutathione Lyase
• Glutathione

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism)
• Cell Membrane Permeability
• Drug Screening Assays, Antitumor
• Drug Stability
• Enzyme Inhibitors (chemistry, metabolism)
• Glutathione (analogs & derivatives, chemistry, metabolism)
• Glutathione Transferase (chemistry)
• Humans
• Kinetics
• Lactoylglutathione Lyase (antagonists & inhibitors)
• Leukemia L1210 (metabolism, pathology)
• Mice
• Mice, Inbred DBA
• Placenta (chemistry)
• Prodrugs (chemical synthesis, chemistry, metabolism)
• Tumor Cells, Cultured