Katrina M Miranda

PMID: 11042174;Abstract:

The nitroxyl anion (NO^-) is a highly reactive molecule that may be involved in pathophysiological actions associated with increased formation of reactive nitrogen oxide species. Angeli's salt (Na2N2O3; AS) is a NO^- donor that has been shown to exert marked cytotoxicity. However, its decomposition intermediates have not been well characterized. In this study, the chemical reactivity of AS was examined and compared with that of peroxynitrite (ONOO^-) and NO/N2O3. Under aerobic conditions, AS and ONOO^- exhibited similar and considerably higher affinities for dihydrorhodamine (DHR) than NO/N2O3. Quenching of DHR oxidation by azide and nitrosation of diaminonaphthalene were exclusively observed with NO/N2O3. Additional comparison of ONOO^- and AS chemistry demonstrated that ONOO^- was a far more potent one-electron oxidant and nitrating agent of hydroxyphenylacetic acid than was AS. However, AS was more effective at hydroxylating benzoic acid than was ONOO^-. Taken together, these data indicate that neither NO/N2O3 nor ONOO^- is an intermediate of AS decomposition. Evaluation of the stoichiometry of AS decomposition and O2 consumption revealed a 1:1 molar ratio. Indeed, oxidation of DHR mediated by AS proved to be oxygen-dependent. Analysis of the end products of AS decomposition demonstrated formation of NO2/^- and NO3/^- in approximately stoichiometric ratios. Several mechanisms are proposed for O2 adduct formation followed by decomposition to NO3/^- or by oxidation of an HN2O3/^- molecule to form NO2/^-. Given that the cytotoxicity of AS is far greater than that of either NO/N2O3 or NO + O2/^-, this study provides important new insights into the implications of the potential endogenous formation of NO^- under inflammatory conditions in vivo.

Diazeniumdiolate-based aspirin prodrugs have previously been shown to retain the anti-inflammatory properties of aspirin while protecting against the common side effect of stomach ulceration. Initial analysis of two new prodrugs of aspirin that also release either nitroxyl (HNO) or nitric oxide (NO) demonstrated increased cytotoxicity toward human lung carcinoma cells compared to either aspirin or the parent nitrogen oxide donor. In addition, cytotoxicity was significantly lower in endothelial cells, suggesting cancer-specific sensitivity. To assess the chemotherapeutic potential of these new prodrugs in breast cancer, we studied their effect both in cultured cells and in a nude mouse model. Both prodrugs reduced growth of breast adenocarcinoma cells more effectively than the parent compounds while not being appreciably cytotoxic in a related non-tumorigenic cell line (MCF-10A). The HNO donor also was more cytotoxic than the related NO donor. The basis for the observed specificity was investigated in terms of impact on metabolism, DNA damage and repair, apoptosis, angiogenesis and metastasis. The results suggest a significant pharmacological potential for treatment of breast cancer.

Nitroxyl (HNO) donors have been shown to elicit a variety of pharmacological responses, ranging from tumoricidal effects to treatment of heart failure. Isopropylamine-based diazeniumdiolates have been shown to produce HNO on decomposition under physiological conditions. Herein, we report the synthesis and HNO release profiles of primary alicyclic amine-based diazeniumdiolates. These compounds extend the range of known diazeniumdiolate-based HNO donors. Acetoxymethyl ester-protected diazeniumdiolates were also synthesized to improve purification and cellular uptake. The acetoxymethyl derivative of cyclopentylamine diazeniumdiolate not only showed higher cytotoxicity toward cancer cells as compared to the parent anion but was also effective in combination with tamoxifen for targeting estrogen receptor α-negative breast cancer cells.

PMID: 18682867;Abstract:

The synthesis of [Ru(NO2)L(bpy)2]⁺ (bpy = 2,2′-bipyridine and L = pyridine (py) and pyrazine (pz)) can be accomplished by addition of [Ru(NO)L(bpy)2](PF6) 3 to aqueous solutions of physiological pH. The electrochemical processes of [Ru(NO2)L(bpy)2]⁺ in aqueous solution were studied by cyclic voltammetry and differential pulse voltammetry. The anodic scan shows a peak around 1.00 V vs. Ag/AgCl attributed to the oxidation process centered on the metal ion. However, in the cathodic scan a second peak around -0.60 V vs. Ag/AgCl was observed and attributed to the reduction process centered on the nitrite ligand. The controlled reduction potential electrolysis at -0.80 V vs. Ag/AgCl shows NO release characteristics as judged by NO measurement with a NO-sensor. This assumption was confirmed by ESI/MS⁺ and spectroelectrochemical experiment where cis-[Ru(bpy) 2L(H2O)]²⁺ was obtained as a product of the reduction of cis-[Ru^II(NO2)L(bpy)2] ⁺. The vasorelaxation observed in denuded aortic rings pre-contracted with 0.1 μmol L^-1 phenylephrine responded with relaxation in the presence of cis-[Ru^II(NO2)L(bpy)2]⁺. The potential of rat aorta cells to metabolize cis-[Ru^II(NO 2)L(bpy)2]⁺ was also followed by confocal analysis. The obtained results suggest that NO release happens by reduction of cis-[Ru^II(NO2)L(bpy)2]⁺ inside the cell. The maximum vasorelaxation was achieved with 1 × 10^-5 mol L^-1 of cis-[Ru^II(NO2)L(bpy)2] ⁺ complex. © 2008 The Royal Society of Chemistry.