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 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).
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sylvie DUCKI reports financial support, administrative support, equipment, drugs, or supplies, travel, and writing assistance were provided by Laboratoires Servier SAS Research Centre Croissy-sur-Seine. Sylvie DUCKI reports financial support, administrative support, equipment, drugs, or supplies, and travel were provided by French National Research Agency. Sylvie DUCKI reports financial support, administrative support, and equipment, drugs, or supplies were provided by Université of Clermont Auvergne ISITE.
(Copyright © 2022. Published by Elsevier Masson SAS.)