Prodrugs of Nitroxyl as Potential Aldehyde Dehydrogenase Inhibitors vis-a-vis Vascular Smooth Muscle Relaxants

Abstract

The synthesis and the chemical/biological properties of N-hydroxysaccharin (1) (2-hydroxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide), a nitroxyl prodrug, are described. When treated with 0.1 M aqueous NaOH, 1 liberated nitroxyl (HN=O), a known inhibitor of aldehyde dehydrogenase (AlDH), in a time-dependent manner. Nitroxyl was measured gas chromatographically as its dimerization/dehydration product N2O. Under these conditions, Piloty's acid (benzenesulfohydroxamic acid) also gave rise to HNO. However, whereas Piloty's acid liberated finite quantities of nitroxyl when incubated in physiological phosphate buffer, pH 7.4, formation of nitroxyl from 1 was minimal. This was reflected in the differential inhibition of yeast AlDH (IC50 = 48 and > 1000 microM) and the differential relaxation of preconstricted rabbit aortic rings in vitro (EC50 = 1.03 and 14.0 microM) by Piloty's acid and 1, respectively. The O-acetyl derivative of 1, viz., N-acetoxysaccharin (13a), was much less active in both assays. It is concluded that N-hydroxysaccharin (1) is relatively stable at physiological pH and liberates nitroxyl appreciably only at elevated pH's. As a consequence, neither 1 nor its O-methyl (8a) and O-benzyl (8b) derivatives were effective AlDH inhibitors in vivo when administered to rats at 1.0 mmol/kg.

Aerobic Oxidation of Cycloalkanes, Alcohols and Ethylbenzene Catalyzed by the Novel Carbon Radical Chain Promoter NHS (N‐Hydroxysaccharin)

“…In accordance with the mechanism proposed by Ishii and co-workers [5] the carbon radical chain promoter (NHPI or NHS) is involved in two chain propagation steps (see Scheme 5). Table 7.…”

“…[4] We reasoned that the use of Nhydroxysaccharin (NHS; 1b), [5] in which one carbonyl group (CO) is replaced by the more electron-withdrawing sulphonyl (SO 2 ) group, could provide an even more effective carbon radical chain promoter (CRCP). [6] In the course of our study on the oxidation of large ring cycloalkanes with molecular oxygen we found that NHS was an efficient catalyst in combination with cobalt salts.…”

Formation of Nitroxyl and Hydroxyl Radical in Solutions of Sodium Trioxodinitrate

“…It is tempting to speculate that the cytotoxicity of HNO released from 1b could be amplified by its conversion to ⅐ OH in ischemia-acidified tissue (64). However, further studies are needed to understand the effects of HNO in biological systems, as well as to advance the mechanistic algorithms for interpretation and prediction of the cytotoxicity of HNO-releasing prodrugs such as Na 2 N 2 O 3 , derivatives of nitrosobenzene (10), benzisothiazol (66), chloropropamide (67), and N-hydroxybenzene carboximidate (68). …”

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…However, contrary to expectations, extremely low concentrations of nitroxyl deactivate select thiol proteins, such as glyceraldehyde 3-phosphate dehydrogenase, without altering the cellular GSH/GSSG ratio (DeMaster et al, 1998;Paolocci et al, 2007). Pro-drugs of nitroxyl, such as derivatives of N,O-diacylated N-hydroxyarylsulfonamide (Fukuto et al, 1992) and N-acyloxy-Oarenesulfonylated benzenecarboximidic acid (Lee et al, 2001), are being developed, albeit with more emphasis on their use as vasodilators (Nagasawa et al, 1995) that are bioactivated by the esterase activity of the ALDH enzyme. In the treatment of alcohol addiction, cyanamide is a second-line drug relative to disulfiram owing to its greater capacity to induce liver injury compared with disulfiram (Tamai et al, 2000).…”