Prodrugs of nitroxyl and nitrosobenzene as cascade latentiated inhibitors of aldehyde dehydrogenase.
The prototypic aromatic C-nitroso compound, nitrosobenzene (NB), was shown previously to mimic the effect of nitroxyl (HN=O), the putative active metabolite of cyanamide, in inhibiting aldehyde dehydrogenase (AlDH). To minimize the toxicity of NB in vivo, pro-prodrug forms of NB, which were designed to be bioactivated either by an esterase intrinsic to AlDH or the mixed function oxidase enzymes of liver microsomes, were prepared. Accordingly, the prodrug N-benzenesulfonyl-N-phenylhydroxylamine (3) was further latentiated by conversion to its O-acetyl (1a), O-methoxycarbonyl (1b), O-ethoxycarbonyl (1c), and O-methyl (2) derivatives. Similarly, pro-prodrug forms of nitroxyl were prepared by derivatization of the hydroxylamino moiety of methanesulfohydroxamic acid with N, O-bis-acetyl (7a), N,O-bis-methoxycarbonyl (7b), N, O-bis-ethoxycarbonyl (7c), and N-methoxycarbonyl-O-methyl (7d) groups. It was expected that the bioactivation of these prodrugs would initiate a cascade of nonenzymatic reactions leading to the ultimate liberation of NB or nitroxyl, thereby inhibiting AlDH. Indeed, the ester pro-prodrugs of both series were highly active in inhibiting yeast AlDH in vitro with IC50 values ranging from 21 to 64 microM. However, only 7d significantly raised ethanol-derived blood acetaldehyde levels when administered to rats, a reflection of the inhibition of hepatic mitochondrial AlDH-2.
Conway
T T
TT
Minneapolis VA Medical Center; Department of Chemistry, St. Cloud State University; and the Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55417, USA.
DeMaster
E G
EG
Lee
M J
MJ
Nagasawa
H T
HT
D000079:Acetaldehyde / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008297:Male; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013552:Swine; D015003:Yeasts / Q000201:enzymology
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D011355:Prodrugs; D013449:Sulfonamides; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; C039900:nitroxyl; D000079:Acetaldehyde; C012456:nitrosobenzene