Cantharimides: a new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A

Bioorg Med Chem Lett. 2001 Nov 19;11(22):2941-6. doi: 10.1016/s0960-894x(01)00594-7.

Abstract

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a D- or L-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC(50)=3.22+/-0.7 microM; PP2A IC(50)=0.81+/-0.1 microM and PP1 IC(50)=2.82+/-0.6 microM; PP2A IC(50)=1.35+/-0.3 microM, respectively) than norcantharidin (PP1 IC(50)=5.31+/-0.76 microM; PP2A IC(50)=2.9+/-1.04 microM) and essentially equipotent with cantharidin (PP1 IC(50)=3.6+/-0.42 microM; PP2A IC(50)=0.36+/-0.08 microM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Cantharidin / analogs & derivatives
  • Cantharidin / chemical synthesis
  • Cantharidin / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Histidine / chemistry
  • Models, Molecular
  • Molecular Structure
  • Phosphoprotein Phosphatases / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Enzyme Inhibitors
  • Histidine
  • norcantharidin
  • Phosphoprotein Phosphatases
  • Cantharidin