Broad-Spectrum Anti-Cancer Activity of O-Arylated Diazeniumdiolates.

O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) and O(2)-{2,4-dinitro-5-[4-(N-methylamino)be nzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO) are O(2)-arylated diazeniumdiolates that have shown promising in vivo activity in a variety of rodent cancer models, including prostate cancer, leukemia, liver cancer, multiple myeloma, and ovarian cancer. This compound class was designed to be activated for anti-cancer effects by glutathione-S-transferase (GST)-induced release of cytotoxic nitric oxide (NO), but mechanistic studies have implicated a variety of pathways, some GST/NO-related, some not. Current work is focused on improving formulations and other drug development activities, as well as exploring possible new applications of these agents and their analogs. The selectivity of these drugs for attacking tumors while exhibiting little toxicity toward normal tissues suggests considerable promise for the treatment of various tumor types.