Synthesis of optically pure norcantharidin analogue NCA-01, a highly selective protein phosphatase 2B inhibitor, and its derivatives

Chem Asian J. 2012 Jun;7(6):1221-30. doi: 10.1002/asia.201200077. Epub 2012 Apr 5.

Abstract

An efficient synthetic route to optically pure norcantharidin analogue NCA-01, a highly selective inhibitor of protein phosphatase 2B (PP2B; calcineurin), has been developed. The absolute stereochemistry of the enantiomers was determined by X-ray crystallographic analysis. Optically pure NCA derivatives that had various substituents at the C1 position were synthesized in a similar manner. The PP2B-inhibitory activities of NCA-01 and its derivatives were independent of the enantiomeric form. NCA-01 dimethyl ester potently inhibited IL-2 production in Jurkat cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Calcineurin / metabolism
  • Calcineurin Inhibitors*
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interleukin-2 / metabolism
  • Jurkat Cells
  • Protein Structure, Tertiary
  • Stereoisomerism

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Calcineurin Inhibitors
  • Enzyme Inhibitors
  • Interleukin-2
  • NCA-01
  • norcantharidin
  • Calcineurin