PRODRUGS OF NITROXYL AS INHIBITORS OF ALDEHYDE DEHYDROGENASE
PRODRUGS OF NITROXYL AS INHIBITORS OF ALDEHYDE DEHYDROGENASE
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DOI：
10.1021/jm00098a008
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发表时间：
1992-10-02
影响因子：
7.3
通讯作者：
DEMASTER, EG
中科院分区：
文献类型：
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作者：
LEE, MJC;NAGASAWA, HT;DEMASTER, EG
在之前的论文中，磺酰胺氮上带有OMe取代基的氯丙酰胺类似物被证明可以抑制乙醛脱氢酶（AlDH），并推测这些化合物通过O-去甲基化作用被生物激活，释放出硝酰基（HN=O，亚硝酰氢），这是AlDH的抑制剂。现在提出了由磺酰胺氮上带有 O-酰基而不是 OMe 的化合物产生硝酰基的进一步证据。因此，一氧化二氮（N2O），即硝酰基二聚和歧化的最终产物，被发现是在N,O-二酰基化的N-羟基芳基磺酰胺的碱水解或酶水解中产生的。由于后一种化合物在被酵母 AlDH 固有的酯酶生物激活后在体外强烈抑制该酶，因此这些化合物产生的硝酰基必定是抑制 AlDH 的常见中间体。
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.