title: N-hydroxybenzenecarboximidic acid derivatives: a new class of nitroxyl-generating prodrugs.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Lee
authors.forename: D W
authors.initials: DW
authors.lastname: Shoeman
authors.forename: D J
authors.initials: DJ
authors.lastname: Goon
authors.forename: H T
authors.initials: HT
authors.lastname: Nagasawa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D004950:Esterases / Q000378:metabolism; D006868:Hydrolysis; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry*; D007202:Indicators and Reagents; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009589:Nitrogen Oxides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*; D013552:Swine
chemical_list: D000975:Antioxidants; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D009589:Nitrogen Oxides; D011355:Prodrugs; D013449:Sulfonamides; C097220:Piloty's acid; D004950:Esterases; C039900:nitroxyl