Synthesis and biological evaluation of desmethylveramiline, a micromolar Hedgehog inhibitor

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3608-12. doi: 10.1016/j.bmcl.2011.04.103. Epub 2011 Apr 29.

Abstract

Desmethylveramiline (1), an aza steroid analogue of veramiline was designed as a surrogate for cyclopamine, a reference antagonist of the Sonic Hedgehog (Shh) pathway. Desmethyveramiline (1) was prepared in seven steps from commercially available Fernholtz acid using the hydroformylation of a terminal olefine as the key step for the construction of the piperidine appendage. In two assays (i) the inhibition of the Shh-induced Gli-dependent luciferase activity in Shh-light2 cells, (ii) the inhibition of the SAG-induced differentiation of the mesenchymal C3H10T1/2 cells, desmethylveramiline (1) is an inhibitor in the μM range comparable to cyclopamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cholesterol / analogs & derivatives*
  • Cholesterol / chemical synthesis
  • Cholesterol / chemistry
  • Cholesterol / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hedgehog Proteins / antagonists & inhibitors*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • NIH 3T3 Cells
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Signal Transduction / drug effects*
  • Veratrum Alkaloids / pharmacology

Substances

  • Enzyme Inhibitors
  • Hedgehog Proteins
  • Piperidines
  • Veratrum Alkaloids
  • desmethylveramiline
  • Cholesterol
  • cyclopamine