Lee M J, Nagasawa H T, Elberling J A, DeMaster E G
Department of Medicinal Chemistry, University of Minnesota, Minneapolis.
J Med Chem. 1992 Oct 2;35(20):3648-52. doi: 10.1021/jm00098a008.
In the preceding paper, analogs of chlorpropamide with an OMe substituent on the sulfonamide nitrogen were shown to inhibit aldehyde dehydrogenase (AlDH), and it was postulated that these compounds were bioactivated by O-demethylation to release nitroxyl (HN = O, nitrosyl hydride), which is an inhibitor of AlDH. Further evidence for the production of nitroxyl from compounds with O-acyl instead of OMe on the sulfonamide nitrogen is now presented. Thus, nitrous oxide (N2O), the end product of nitroxyl dimerization and disproportionation, was found to be generated on alkaline or enzymatic hydrolysis of N,O-diacylated N-hydroxyarylsulfonamides. Since the latter compounds strongly inhibit yeast AlDH in vitro after bioactivation by an esterase intrinsic to this enzyme, nitroxyl generated from these compounds must be the common intermediate that inhibits AlDH.
在前一篇论文中，已表明在磺酰胺氮上带有甲氧基取代基的氯磺丙脲类似物可抑制醛脱氢酶（AlDH），并且据推测这些化合物通过O-去甲基化进行生物活化以释放硝酰（HN = O，氢亚硝基），它是AlDH的一种抑制剂。现在提供了关于在磺酰胺氮上带有O-酰基而非甲氧基的化合物产生硝酰的进一步证据。因此，发现硝酰二聚化和歧化的终产物一氧化二氮（N₂O）是在N,O-二酰化N-羟基芳基磺酰胺进行碱性或酶促水解时生成的。由于后一类化合物在被该酶固有的酯酶进行生物活化后在体外强烈抑制酵母AlDH，由这些化合物产生的硝酰必定是抑制AlDH的共同中间体。
