Nagasawa H T, Kawle S P, Elberling J A, DeMaster E G, Fukuto J M
VA Medical Center, Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55417, USA.
J Med Chem. 1995 May 26;38(11):1865-71. doi: 10.1021/jm00011a005.
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.
描述了硝酰基前药N-羟基糖精（1）（2-羟基-1,2-苯并异噻唑-3(2H)-酮1,1-二氧化物）的合成及其化学/生物学性质。用0.1 M氢氧化钠水溶液处理时，1以时间依赖性方式释放出硝酰基（HN=O），醛脱氢酶（AlDH）的一种已知抑制剂。硝酰基以其二聚化/脱水产物N2O通过气相色谱法进行测定。在这些条件下，皮洛蒂酸（苯磺基异羟肟酸）也会产生HNO。然而，当在pH 7.4的生理磷酸盐缓冲液中孵育时，皮洛蒂酸释放出有限量的硝酰基，而1产生的硝酰基极少。这分别反映在皮洛蒂酸和1对酵母AlDH的差异抑制（IC50 = 48和>1000 microM）以及对预收缩兔主动脉环的体外差异舒张（EC50 = 1.03和14.0 microM）上。1的O-乙酰基衍生物，即N-乙酰氧基糖精（13a），在这两种测定中活性都低得多。得出的结论是，N-羟基糖精（1）在生理pH下相对稳定，仅在较高pH下才会明显释放硝酰基。因此，当以1.0 mmol/kg的剂量给大鼠给药时，1及其O-甲基（8a）和O-苄基（8b）衍生物在体内均不是有效的AlDH抑制剂。
