Synthesis and characterization of an N-acylsulfonamide inhibitor of human asparagine synthetase

Org Lett. 2003 Jun 12;5(12):2033-6. doi: 10.1021/ol034212n.

Abstract

[structure: see text] The synthesis of N-acylsulfonamide 6, which is an analogue of beta-aspartyl-AMP, is described. This compound appears to be the first and only potent inhibitor of human asparagine synthetase that has been described to date. The N-acylsulfonamide 6 exhibits slow-onset inhibition kinetics, with a K(i) of 728 nM. Preparation and characterization of two additional N-acylsulfonamide analogues has also demonstrated the importance of hydrogen-bonding interactions in the recognition of the AS inhibitor with the enzyme. These observations provide the basis for the discovery of new compounds with application in the treatment of drug-resistant leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartate-Ammonia Ligase / antagonists & inhibitors*
  • Aspartate-Ammonia Ligase / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Organophosphorus Compounds / analysis
  • Organophosphorus Compounds / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Enzyme Inhibitors
  • Organophosphorus Compounds
  • Recombinant Proteins
  • Sulfonamides
  • Aspartate-Ammonia Ligase