Prodrugs of Nitroxyl as Inhibitors of Aldehyde Dehydrogenase

J Med Chem. 1992 Oct 2;35(20):3648-52. doi: 10.1021/jm00098a008.

Abstract

In the preceding paper, analogs of chlorpropamide with an OMe substituent on the sulfonamide nitrogen were shown to inhibit aldehyde dehydrogenase (AlDH), and it was postulated that these compounds were bioactivated by O-demethylation to release nitroxyl (HN = O, nitrosyl hydride), which is an inhibitor of AlDH. Further evidence for the production of nitroxyl from compounds with O-acyl instead of OMe on the sulfonamide nitrogen is now presented. Thus, nitrous oxide (N2O), the end product of nitroxyl dimerization and disproportionation, was found to be generated on alkaline or enzymatic hydrolysis of N,O-diacylated N-hydroxyarylsulfonamides. Since the latter compounds strongly inhibit yeast AlDH in vitro after bioactivation by an esterase intrinsic to this enzyme, nitroxyl generated from these compounds must be the common intermediate that inhibits AlDH.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldehyde Dehydrogenase / antagonists & inhibitors*
  • Animals
  • Enzyme Inhibitors / pharmacology*
  • Liver / drug effects
  • Liver / enzymology
  • Nitrogen Oxides / metabolism*
  • Prodrugs / pharmacology*
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Swine

Substances

  • Enzyme Inhibitors
  • Nitrogen Oxides
  • Prodrugs
  • Sulfonamides
  • Aldehyde Dehydrogenase
  • nitroxyl