Synthesis, mechanistic studies, and anti-proliferative activity of glutathione/glutathione S-transferase-activated nitric oxide prodrugs.

Abstract

Nitric oxide (NO) prodrugs such as O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) are a growing class of promising NO-based therapeutics. Nitric oxide release from the anti-cancer lead compound, JS-K, is proposed to occur through a nucleophilic aromatic substitution by glutathione (GSH) catalyzed by glutathione S-transferase (GST) to form a diazeniumdiolate anion that spontaneously releases NO. In this study, a number of structural analogues of JS-K were synthesized and their chemical and biological properties were compared with those of JS-K. The homopiperazine analogue of JS-K showed anti-cancer activity that is comparable with that of JS-K but with a diminished reactivity towards both GSH and GSH/GST; both the aforementioned compounds displayed no cytotoxic activity towards normal renal epithelial cell line at concentrations where they significantly diminished the proliferation of a panel of renal cancer cell lines. These properties may prove advantageous in the further development of this class of nitric oxide prodrugs as cancer therapeutic agents.

• Authors: Harinath Chakrapani, Ravi C Kalathur, Anna E Maciag, Michael L Citro, Xinhua Ji, Larry K Keefer, Joseph E Saavedra
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 16 Issue 22 Pg. 9764-71 (Nov 15 2008) ISSN: 1464-3391 [Electronic] England
• PMID: 18930407 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Antineoplastic Agents
• Azo Compounds
• Nitric Oxide Donors
• O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate
• Piperazines
• Prodrugs
• diazeniumdiolate
• Nitric Oxide
• Glutathione Transferase
• Glutathione

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Azo Compounds (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Glutathione (metabolism)
• Glutathione Transferase (metabolism)
• HL-60 Cells
• Humans
• Mice
• Nitric Oxide (metabolism)
• Nitric Oxide Donors
• Piperazines (chemical synthesis, chemistry, pharmacology)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• U937 Cells