8-Aza-immucillins as transition-state analogue inhibitors of purine nucleoside phosphorylase and nucleoside hydrolases

J Med Chem. 2003 Jan 2;46(1):155-60. doi: 10.1021/jm0203332.

Abstract

The 8-aza-immucillins (8-aza-9-deazapurines linked from C9 to C1 of 1,4-dideoxy-1,4-iminoribitol) have been designed as transition-state analogues of the reactions catalyzed by purine nucleoside phosphorylase and nucleoside hydrolases. Syntheses of the 8-aza-immucillin analogues of inosine and adenosine are described. They are powerful inhibitors of the target enzymes with equilibrium dissociation constants as low as 42 pM.

Publication types

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

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / chemical synthesis
  • Adenosine / chemistry
  • Animals
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Cattle
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Humans
  • Inosine / analogs & derivatives
  • Inosine / chemical synthesis
  • Inosine / chemistry
  • N-Glycosyl Hydrolases / antagonists & inhibitors
  • Purine Nucleosides / chemical synthesis*
  • Purine Nucleosides / chemistry
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Enzyme Inhibitors
  • Purine Nucleosides
  • Inosine
  • Purine-Nucleoside Phosphorylase
  • N-Glycosyl Hydrolases
  • Adenosine