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

  1. Author:
    Chakrapani, H.
    Kalathur, R. C.
    Maciag, A. E.
    Citro, M. L.
    Ji, X. H.
    Keefer, L. K.
    Saavedra, J. E.

  2. Author Address

    Chakrapani, Harinath, Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. [Kalathur, Ravi C.; Ji, Xinhua] NCI, Macromol Crystallog Sect, Biomol Struct Sect, Frederick, MD 21702 USA. [Maciag, Anna E.; Citro, Michael L.; Saavedra, Joseph E.] NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA.
    1. Year: 2008
  2. Journal: Bioorganic & Medicinal Chemistry
    1. 16
    2. 22
    3. Pages: 9764-9771
  4. Type of Article: Article
  1. 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. Published by Elsevier Ltd.

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External Sources

  1. PMID: 18930407

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