Total synthesis of two novel subpicomolar sarco/endoplasmatic reticulum Ca2+-ATPase inhibitors designed by an analysis of the binding site of thapsigargin

J Med Chem. 2005 Nov 3;48(22):7005-11. doi: 10.1021/jm058036v.

Abstract

Analysis of molecular interaction fields based on the published crystal structure of thapsigargin bound to the sarco/endoplasmatic reticulum Ca(2+)-ATPase and analysis of the volume and shape of the ligand binding site and of the SERCA-thapsigargin interactions have enabled design of two new compounds inhibiting SERCA in the subpicomolar range. The two inhibitors were synthesized using (S)-carvone as starting material and found to be 3 and 10 times more potent than thapsigargin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azulenes / chemical synthesis*
  • Azulenes / chemistry
  • Binding Sites
  • Calcium-Transporting ATPases / antagonists & inhibitors*
  • Calcium-Transporting ATPases / chemistry*
  • Endoplasmic Reticulum / enzymology*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Ligands
  • Models, Molecular*
  • Sarcoplasmic Reticulum / enzymology
  • Stereoisomerism
  • Thapsigargin / chemistry*

Substances

  • 2-methylbut-2-enoic acid 4-butyryloxy-6-ethoxy-3,3a-dihydroxy-3,6,9-trimethyl-2-oxododecahydroazuleno(4,5-b)furan-8-yl ester
  • 2-methylbut-2-enoic acid 6-acetoxy-4-butyryloxy-3,3a-dihydroxy-3,6,9-trimethyl-2-oxododecahydroazuleno(4,5-b)furan-8-yl ester
  • Azulenes
  • Enzyme Inhibitors
  • Ligands
  • Thapsigargin
  • Calcium-Transporting ATPases