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).

Deoxycyanamidation of Alcohols with N-Cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS).

The first one-pot deoxycyanamidation of alcohols has been developed using N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as both a sulfonyl transfer reagent and a cyanamide source, accessing a diverse range of tertiary cyanamides in excellent isolated yields. This approach exploits the underdeveloped desulfonylative (N-S bond cleavage) reactivity pathway of NCTS, which is more commonly employed for electrophilic C- and N-cyanation processes.