Synthesis and biological evaluation of desmethylveramiline, a micromolar Hedgehog inhibitor

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.