Design, synthesis and biological evaluation of conformationnally-restricted analogues of E7010 as inhibitors of tubulin assembly (ITA) and vascular disrupting agents (VDA)

Vascular-disrupting agents (VDA) specifically target established neovasculature which results in vascular shut-down. 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 as-sembly. 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).