The Nitric Oxide Prodrug JS-K and Its Structural Analogues as Cancer Therapeutic Agents

Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O2-(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, O2-(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 O2-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K.