Lee M J, Shoeman D W, Goon D J, Nagasawa H T
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Nitric Oxide. 2001 Jun;5(3):278-87. doi: 10.1006/niox.2001.0349.
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 (13)C 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 N(2)O, as well as the expected arenesulfinic acid and benzoic acid. Alkaline hydrolysis also produced N(2)O, 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.
基于 Piloty 酸生成硝酰基（HNO）的倾向，我们之前制备了多种 N,O-双酰化的 Piloty 酸衍生物，并表明此类前药在酯水解后会发生歧化反应，生成一种不稳定的中间体，该中间体水解生成硝酰基。为了扩展该系列的通用性，我们期望得到一些混合的 N,O-二酰化 Piloty 酸衍生物，并设计了一条合成路线。意外的是，这些努力使我们得到了一系列此前未报道的新型硝酰基生成化合物。因此，苯甲羟肟酸在羟氨基氧上进行酰化反应，所得产物转化为其钠盐。用芳基磺酰氯处理该盐有望得到 Piloty 酸的混合 N,O-二酰化衍生物。然而，得到的产物却是异构的羧亚胺酸衍生物，其结构是根据与 sp(2) 碳相关的红外光谱和 (13)C 核磁共振光谱频率推导出来的。该系列原型化合物的 X 射线晶体结构分析验证了这些结构。当与猪肝酯酶或小鼠血浆一起孵育时，这些 N-酰氧基-O-芳基磺酰化苯甲羧亚胺酸衍生物会释放出以 N(2)O 形式测定的 HNO，以及预期的芳基亚磺酸和苯甲酸。碱性水解也会产生 N(2)O，但主要产物是芳基磺酸和苯甲羟肟酸。因此，这些 N-羟基苯甲羧亚胺酸衍生物代表了一类新型的硝酰基前药，在释放硝酰基之前需要酶促生物活化。
