Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition

J Am Chem Soc. 2003 Dec 24;125(51):15694-5. doi: 10.1021/ja038672n.


Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.

Publication types

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

MeSH terms

  • Alkenes / chemistry
  • Alkenes / pharmacology*
  • Amino Acid Sequence
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Lactones / chemistry
  • Lactones / pharmacology
  • Molecular Sequence Data
  • Phosphoprotein Phosphatases / antagonists & inhibitors*
  • Polyenes
  • Pyrones
  • Structure-Activity Relationship


  • Alkenes
  • Enzyme Inhibitors
  • Lactones
  • Polyenes
  • Pyrones
  • Phosphoprotein Phosphatases
  • fostriecin