Diversity-oriented synthesis of pochonins and biological evaluation against a panel of kinases

Chemistry. 2006 Nov 24;12(34):8819-34. doi: 10.1002/chem.200600553.

Abstract

Pochonins A-F were recently characterized as six new members of the naturally occurring family of 14-membered resorcylic acid lactones. As there are a high number of ATPase and kinase inhibitors among natural resorcylic lactones, a library based on the pochonin scaffold, with five points of diversity, was prepared which includes diversity beyond that of the natural analogues. The library was synthesized by using solid-supported reagents amenable to automation. Testing the library for its inhibition against a panel of 24 kinases at 10 microM afforded a >14 % hit rate. These results demonstrate the potential of the resorcylides towards the inhibition of therapeutically relevant kinases.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors
  • Adenosine Triphosphatases / metabolism
  • Drug Design
  • Enzyme Inhibitors / pharmacology
  • Lactones / chemical synthesis
  • Lactones / pharmacology*
  • Macrolides / chemical synthesis
  • Macrolides / pharmacology*
  • Phosphotransferases / antagonists & inhibitors
  • Phosphotransferases / metabolism*
  • Resorcinols / chemistry
  • Resorcinols / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Lactones
  • Macrolides
  • Resorcinols
  • Phosphotransferases
  • Adenosine Triphosphatases