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Antitumor activity of JS-K O-2-(2,4-dinitrophenyl) 1- (4-ethoxycarbonyl)piperazin-1-yl diazen-1-ium-1,2-diolate and related O-2-Aryl diazeniumdiolates in vitro and in vivo

  1. Author:
    Shami, P. J.
    Saavedra, J. E.
    Bonifant, C. L.
    Chu, J. X.
    Udupi, V.
    Malaviya, S.
    Carr, B. I.
    Kar, S.
    Wang, M. F.
    Jia, L.
    Ji, X. H.
    Keefer, L. K.

  2. Author Address

    Natl Canc Inst, Basic Res Program, SAIC Frederick, Chem Sect,Lab Comparat Carcinogenesis, Frederick, MD 21702 USA. Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ Utah, Dept Internal Med, Div Med Oncol, Salt Lake City, UT 84112 USA. Univ Pittsburgh, Liver Canc Ctr, Pittsburgh, PA 15213 USA. Natl Canc Inst, Dev Therapeut Program, Rockville, MD 20852 USA.;Keefer, LK, Natl Canc Inst, Basic Res Program, SAIC Frederick, Chem Sect,Lab Comparat Carcinogenesis, Frederick, MD 21702 USA.;keefer@ncifcrf.gov
    1. Year: 2006
    2. Date: Jul
  2. Journal: Journal of Medicinal Chemistry
    1. 49
    2. 14
    3. Pages: 4356-4366
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    The literature provides evidence that metabolic nitric oxide ( NO) release mediates the cytotoxic activities ( against human leukemia and prostate cancer xenografts in mice) of JS-K, a compound of structure R2N-(O)=NO-Ar for which R2N is 4-(ethoxycarbonyl) piperazin-1-yl and Ar is 2,4-dinitrophenyl. Here we present comparative data on the potencies of JS-K and 41 other O-2-arylated diazeniumdiolates as inhibitors of HL-60 human leukemia cell proliferation, as well as in the NCI 51-cell-line screen for six of them. The data show JS-K to be the most potent of the 42 in both screens and suggest that other features of its structure and metabolism besides NO release may contribute importantly to its activity. Results with control compounds implicate JS-K's arylating ability, and the surprisingly low IC50 value of the N-(ethoxycarbonyl) piperazine byproduct of NO release suggests a role for the R2N moiety. In addition to the above-mentioned in vivo activities, JS-K is shown here to be carcinostatic in a rat liver cancer model.

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External Sources

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  2. DOI: 10.1021/jm060022h
  3. View record in Web of Science®
  4. WOS: 000238805800038

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