N-Hydroxybenzenecarboximidic Acid Derivatives: A New Class of Nitroxyl-Generating Prodrugs

• Published in: Nitric oxide Vol. 5; no. 3; pp. 278 - 287
• Main Authors: Lee, Melinda J.C., Shoeman, Don W., Goon, David J.W., Nagasawa, Herbert T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2001
• Subjects: 13C NMR; Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacokinetics; benzenesulfinic acid; benzohydroxamic acid; Crystallography, X-Ray; Esterases - metabolism; Hydrolysis; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Indicators and Reagents; Liver - enzymology; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Molecular Conformation; N-hydroxybenzenecarboximidic acids; Nitrogen Oxides - chemical synthesis; Nitrogen Oxides - chemistry; Nitrogen Oxides - pharmacokinetics; nitroxyl; Piloty's acid; prodrugs; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Spectrophotometry, Infrared; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Swine; Piloty's acid; benzenesulfinic acid; N-hydroxybenzenecarboximidic acids; nitroxyl; prodrugs; benzohydroxamic acid; 13C NMR
• ISSN: 1089-8603; 1089-8611
• 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 13C NMR spectral frequencies associated with the sp2 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 andbenzohydroxamic acid. Thus, these N-hydroxybenzenecarboximidic acid derivatives represent a new series of nitroxyl prodrugs that require enzymatic bioactivation before nitroxyl can be liberated.