PRODRUGS OF NITROXYL AND NITROSOBENZENE AS CASCADE LATENTIATED INHIBITORS OF ALDEHYDE DEHYDROGENASE

The prototypic aromatic C-nitroso compound, nitrosobenzene (NB), was s hown previously to mimic the effect of nitroxyl (HN=O), the putative a ctive metabolite of cyanamide, in inhibiting aldehyde dehydrogenase (A lDH). To minimize the toxicity of NE in vivo, pro-prodrug forms of NE, which were designed to be bioactivated either by an esterase intrinsi c to AlDH or the mixed function oxidase enzymes of liver microsomes, w ere prepared. Accordingly, the prodrug N-benzenesulfonyl-N-phenylhydro xylamine (3) was further latentiated by conversion to its O-acetyl (1a ), O-methoxycarbonyl (1b), O-ethoxycarbonyl (1c), and O-methyl (2) der ivatives. Similarly, pro-prodrug forms of nitroxyl were prepared by de rivatization of the hydroxylamino moiety of methanesulfohydroxamic aci d with N,O-bis-acetyl (7a), N,O-bis-methoxycarbonyl (7b), N,O-bis-etho xycarbonyl (7c), and N-methoxycarbonyl-O-methyl (7d) groups. It was ex pected that the bioactivation of these prodrugs would initiate a casca de of nonenzymatic reactions leading to the ultimate liberation of NE or nitroxyl, thereby inhibiting AIDH. Indeed, the ester pro-prodrugs o f both series were highly active in inhibiting yeast AlDH in vitro wit h IC50 values ranging from 21 to 64 mu M. However, only 7d significant ly raised ethanol-derived blood acetaldehyde levels when administered to rats, a reflection of the inhibition of hepatic mitochondrial AlDH- 2.