RESUMO
Vascular-disrupting agents (VDA) specifically target established neovasculature which results in vascular shutdown. This therapeutic strategy could improve the outcome of pathologies involving aberrant angiogenesis. Although several classes of VDA exist, inhibitors of tubulin assembly (ITA) represent the main category. A series of 21 conformationnally-restricted analogues of E7010, a known ITA-VDA, were designed and synthesised as novel inhibitors of tubulin assembly (ITA) and vascular-disrupting agents (VDA). Among them, indole 4j exhibited good potency against HUVEC and HIG-82 cell lines, as well as a good ability to inhibit tubulin assembly. Furthermore, indole 4j reduced HUVEC migration in a dose-dependent manner, indicating a vascular disrupting activity comparable to that of the gold standard, Combretastatin A4 (CA4).
Assuntos
Antineoplásicos , Tubulina (Proteína) , Tubulina (Proteína)/metabolismo , Linhagem Celular Tumoral , Moduladores de Tubulina , Antineoplásicos/farmacologia , Indóis/farmacologia , Inibidores da Angiogênese/farmacologiaRESUMO
The straightforward entry to benzofuroindoline containing natural product-like scaffolds has been achieved by a challenging [3 + 2] oxidative coupling between phenols and indoles. The reaction proceeds by NIS-oxidation of the indole followed by the trapping of the resulting electrophilic intermediate by phenol.