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.

Bcl-2 antagonist apogossypol (NSC736630) displays single-agent activity in Bcl-2–transgenic mice and has superior efficacy with less toxicity compared with gossypol (NSC19048)

“…21 Cells were grown in RPMI 1640 culture medium supplemented with 5% FBS and 2 mM L-glutamine for 24 hours at 37°C to allow stabilization prior to addition of gossypol and apogossypol. Stock solutions of gossypol and apogossypol in DMSO were serially diluted with the RPMI 1640 medium and added immediately to the microtiter plates to produce 5 concentrations of the compounds: 10 Ϫ4 , 10 Ϫ5 , 10 Ϫ6 , 10 Ϫ7 , and 10 Ϫ8 M. The compounds were incubated with cells for 48 hours before fixing cells in situ using 10% trichloroacetic acid.…”

“…Molar concentrations of gossypol or apogossypol that caused 50% growth inhibition (GI 50 ) and 50% cell killing (LC 50 ) of the cell lines were determined as described. 21 GI50 data for apogossypol and gossypol were compared by Spearman correlation analysis. LD50 data were compared by chi-square test, empirically dichotomizing into resistant (LD50 Ͻ 100 M) and sensitive (LD50 Ͼ 100 M) categories.…”

Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound

“…PABA/NO and several ester derivatives (9)(10)(11)(12)(13)(14) differing in the substitution pattern in the aroate ester functionality were synthesized in moderate to good yields from 7 or 8 (Table 1).…”

“…17-20 Molecular modeling studies of the Meisenheimer complex (Scheme 1) were used as a guide in the design of GSTπ-selective 2,4-dinitroaryl derivatives of DMA/NO (Structure 2 , Scheme 2). [12][13][14] One such compound, PABA/NO (Structure 3, Scheme 2), has shown tumoristatic activity against A2780 human ovarian cancer xenografts in female SCID mice with a potency comparable to that of cisplatin. 14 This and other in vitro and in vivo activities established PABA/NO to be a promising anti-cancer lead compound.…”

Synthesis of Azole-containing Piperazine Derivatives and Evaluation of their Antibacterial, Antifungal and Cytotoxic Activities

“…The incorporation of piperazine is an important synthetic strategy in drug discovery due to its easy modificability, proper alkality, water solubility, the capacity for the formation of hydrogen bonds and adjustment of molecular physicochemical properties. 4,5 A broad range of biological active compounds displaying antibacterial, 3,[6][7][8] antifungal, 9,10 anticancer, [11][12][13] antiparasitic, 14,15 antihistamin, 16 psychotolytic, 17 and antidepressive activities 18 have been also found to contain this versatile core. In particular, structurally simple 1-(1-naphthylmethyl)-piperazine, as the efflux pump inhibitor, could exert positive effect on tetracyclines and ciprofloxacin against their resistant bacteria.…”