PRODRUGS OF NITROXYL AS POTENTIAL ALDEHYDE DEHYDROGENASE INHIBITORS VIS-A-VIS VASCULAR SMOOTH-MUSCLE RELAXANTS

The synthesis and the chemical/biological properties of N-hydroxysacch arin (1) (2-hydroxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide), a nitro xyl prodrug, are described. When treated with 0.1 M aqueous NaOH, 1 li berated nitroxyl (HN = O), a known inhibitor of aldehyde dehydrogenase (AlDH), in a time-dependent manner. Nitroxyl was measured gas chromat ographically as its dimerization/dehydration product N2O. Under these conditions, Piloty's acid (benzene-sulfohydroxamic acid) also gave ris e to HNO. However, whereas Piloty's acid liberated finite quantities o f nitroxyl when incubated in physiological phosphate buffer, pH 7.4, f ormation of nitroxyl from 1 was minimal. This was reflected in the dif ferential inhibition of yeast AlDH (IC50 = 48 and > 1000 mu M) and the differential relaxation of preconstricted rabbit aortic rings in vitr o (EC(50) = 1.03 and 14.0 mu M) 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 app reciably only at elevated pH's. As a consequence, neither 1 nor its O- methyl (8a) and O-benzyl(8b) derivatives were effective AlDH inhibitor s in vivo when administered to rats at 1.0 mmol/kg.