Antitumor activity of JS-K [O2-(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

Paul J. Shami, Joseph E. Saavedra, Challice L. Bonifant, Jingxi Chu, Vidya Udupi, Swati Malaviya, Brian I. Carr, Siddhartha Kar, Meifeng Wang, Lee Jia, Xinhua Ji, Larry K. Keefer

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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-N(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 O2-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.

Original languageEnglish (US)
Pages (from-to)4356-4366
Number of pages11
JournalJournal of medicinal chemistry
Issue number14
StatePublished - Jul 13 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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