title: 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.
authors.affiliation: VA Medical Center, Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55417, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Nagasawa
authors.forename: S P
authors.initials: SP
authors.lastname: Kawle
authors.forename: J A
authors.initials: JA
authors.lastname: Elberling
authors.forename: E G
authors.initials: EG
authors.lastname: DeMaster
authors.forename: J M
authors.initials: JM
authors.lastname: Fukuto
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D001711:Biotransformation; D004355:Drug Stability; D005609:Free Radicals; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009589:Nitrogen Oxides / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012439:Saccharin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D005609:Free Radicals; C094121:N-hydroxysaccharin; D009589:Nitrogen Oxides; D011355:Prodrugs; D000444:Aldehyde Dehydrogenase; D012439:Saccharin; C039900:nitroxyl