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

Abstract

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.

FIGURE 1

O²-Arylated diazeniumdiolate 1 as a prodrug of NO. A nucleophile X^- displaces ionic diazeniumdiolate 2, which then spontaneously releases up to two equivalents of NO at physiological pH.

FIGURE 2

JS-K significantly slowed the rate of prostate xenograft growth (A) and induced necrosis in the remaining tumor mass (B). Note that the tumor tissue shown in the JS-K-treated section at the top shows more necrotic areas than the untreated control tissue section shown at the bottom. (Adapted from Shami et al., 2003.)

FIGURE 3

Intravenously administered JS-K signifi cantly improved survival of mice bearing xenografts of OPM-1 multiple myeloma cells. (Adapted from Kiziltepe et al., 2007. Copyright American Society of Hematology.)

FIGURE 4

Selective inhibitory activity of JS-K against a panel of renal cancer cell lines (TK-10, 786-O, and UO-30) compared with the normal renal epithelial cell line HREpC. (Adapted from Chakrapani et al., 2008.)

FIGURE 5

Metabolic activation pathway converting JS-K to carbamoylated piperazine 5, an arylated thiol moiety 4 (in this case that of GSH under catalysis by GST), and diazeniumdiolate ion 3, which spontaneously hydrolyzes at physiological pH to produce up to two equivalents of NO.

FIGURE 6

Results of molecular modeling experiments leading to the design of PABA/ NO as a potential GSTπ-selective improvement over JS-K. (Reproduced from Saavedra et al., 2006.)