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.
Guillaume Guerlet  1 ,  Thomas Spangenberg ,  André Mann ,  Hélène Faure ,  Martial Ruat
Affiliations
  • 1. Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS-Université de Strasbourg Faculté de Pharmacie, Illkirch, France.
PMID: 21592788 DOI: 10.1016/j.bmcl.2011.04.103
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.