title: Antitumor activity of JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related O2-aryl diazeniumdiolates in vitro and in vivo.
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 R(2)N-N(O)=NO-Ar for which R(2)N 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 IC(50) value of the N-(ethoxycarbonyl)piperazine byproduct of NO release suggests a role for the R(2)N moiety. In addition to the above-mentioned in vivo activities, JS-K is shown here to be carcinostatic in a rat liver cancer model.
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, University of Utah, Salt Lake City, 84112, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shami
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Challice L
authors.initials: CL
authors.lastname: Bonifant
authors.forename: Jingxi
authors.initials: J
authors.lastname: Chu
authors.forename: Vidya
authors.initials: V
authors.lastname: Udupi
authors.forename: Swati
authors.initials: S
authors.lastname: Malaviya
authors.forename: Brian I
authors.initials: BI
authors.lastname: Carr
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Kar
authors.forename: Meifeng
authors.initials: M
authors.lastname: Wang
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Xinhua
authors.initials: X
authors.lastname: Ji
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D008297:Male; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; C452539:diazeniumdiolate