Design and synthesis of O-GlcNAcase inhibitors via 'click chemistry' and biological evaluations

Carbohydr Res. 2011 Jul 1;346(9):1083-92. doi: 10.1016/j.carres.2011.03.026. Epub 2011 Mar 21.

Abstract

Protein O-GlcNAcylation has been shown to play an important role in a number of biological processes, including regulation of the cell cycle, DNA transcription and translation, signal transduction, and protein degradation. O-GlcNAcase (OGA) is responsible for the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from serine or threonine residues, and thus plays a key role in O-GlcNAc metabolism. Potent OGA inhibitors are useful tools for studying the cellular processes of O-GlcNAc, and may be developed as drugs for the treatment neurodegenerative diseases. In this study, Cu(I)-catalyzed 'Click' cycloaddition reactions between glycosyl azides and alkynes were exploited to generate inhibitory candidates of OGA. Enzymatic kinetic screening revealed that compound 7 was a potent competitive inhibitor of human O-GlcNAcase (K(i)=185.6 μM). Molecular docking simulations of compound 7 into CpOGA (Clostridium perfringens OGA) suggested that strong π-π stacking interaction between the compound and W490 considerably contributed to improving the inhibitory activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Click Chemistry*
  • Clostridium perfringens / enzymology
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • N-Acetylglucosaminyltransferases / antagonists & inhibitors*
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase