N-hydroxybenzenecarboximidic acid derivatives:: A new class of nitroxyl-generating prodrugs
N-hydroxybenzenecarboximidic acid derivatives:: A new class of nitroxyl-generating prodrugs
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DOI：
10.1006/niox.2001.0349
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发表时间：
2001-06-01
影响因子：
3.9
通讯作者：
Nagasawa, HT
中科院分区：
文献类型：
--
作者：
Lee, MJC;Shoeman, DW;Nagasawa, HT
根据Piloty酸生成氮氧基(HNO)的倾向，我们以前合成了一些N，O-双酰化Piloty酸的衍生物，发现这类前体药物在酯类水解后发生歧化反应，得到一种不稳定的中间体，该中间体可以水解成氮氧基。为了扩大该系列的通用性，我们需要一些混合的N，O-双酰化Piloty酸衍生物，并设计了一条合成路线。这些努力使我们偶然地发现了一系列迄今为止未被报道的氮氧基生成化合物。因此，苯异羟肟酸与羟胺氧发生酰化反应，生成的产物转化为其钠盐。用芳磺酰氯处理这种盐，有望得到混合的N，O-二酰化的Piloty酸的衍生物。然而，所得到的产物是异构化的羧基二酸衍生物，其结构是根据与sp(2)碳相关的IR和C-13核磁共振谱频率推断的。通过对该系列原型化合物的X-射线晶体结构分析，验证了化合物的结构。当与猪肝酯酶或小鼠血浆孵育时，这些N-酰氧基-O-芳基磺化苯二甲酸衍生物释放出HNO，测量为N2O，以及预期的芳磺酸和苯甲酸。碱解也会产生N2O，但主要产物是芳香酸和苯异羟肟酸。因此，这些N-羟基苯二甲酸衍生物代表了一系列新的氮氧基前药，需要酶生物激活才能释放氮氧基。(C)2001年学术出版社
On the basis of the propensity of Piloty's acid to generate nitroxyl (HNO), we previously prepared a number of N,O-bisacylated Piloty's acid derivatives and showed that such prodrugs underwent a disproportionation reaction following ester hydrolysis to give an unstable intermediate that hydrolyzed to nitroxyl, To expand the versatility of this series, we desired some mixed N,O-diacylated Piloty's acid derivatives and devised a synthetic route to them. Such efforts led us, serendipitously, to a new series of heretofore unreported nitroxyl-generating compounds. Thus, benzohydroxamic acid was acylated on the hydroxylamino oxygen and the resulting product converted to its sodium salt. Treatment of this salt with arenesulfonyl chorides would be expected to give the mixed N,O-diacylated derivatives of Piloty's acid. However, the products obtained were the isomeric carboximidic acid derivatives whose structures were deduced from the IR and C-13 NMR spectral frequencies associated with the sp(2) carbons. The structures were verified by analysis of the X-ray crystal structure of a prototype compound of this series. When incubated with porcine liver esterase or mouse plasma, these N-acyloxy-O-arenesulfonylated benzenecarboximidic acid derivatives liberated HNO, measured as N2O, as well as the expected arenesulfinic acid and benzoic acid. Alkaline hydrolysis also produced N2O, but the major products were the arenesulfonic acid and benzohydroxamic acid. Thus, these N-hydroxybenzenecarboximidic acid derivatives represent a new series of nitroxyl prodrugs that require enzymatic bioactivation before nitroxyl can be liberated. (C) 2001 Academic Press