title: The nitric oxide prodrug JS-K and its structural analogues as cancer therapeutic agents.
abstract: Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O(2)-(2,4-dinitrophenyl) diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates, have been found to show potent anti-proliferative activity in a variety of cancer cells, presumably through the effects of NO. One important member of this class of diazeniumdiolates, O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), has shown promise as a novel cancer therapeutic agent in a number of animal models. This review describes the developments in chemical and biochemical characterization and structure-activity relationship of JS-K and its analogues. In addition, some molecular mechanistic insights into the observed anti-proliferative activity of JS-K are discussed. Finally, a structural motif is presented for O(2)-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K.
authors.affiliation: Basic Science Program, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA. amaciag@ncifcrf.gov
authors.forename: Anna E
authors.initials: AE
authors.lastname: Maciag
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Harinath
authors.initials: H
authors.lastname: Chakrapani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001391:Azo Compounds / Q000737:chemistry / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008968:Molecular Conformation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000627:therapeutic use*; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use*; D011355:Prodrugs / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D020030:Nitric Oxide Donors; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; D011355:Prodrugs