Synthesis and biological evaluation of cis-locked vinylogous combretastatin-A4 analogues: derivatives with a cyclopropyl-vinyl or a cyclopropyl-amide bridge.

Nancy Ty , Julia Kaffy , Alban Arrault (1) , Sylviane Thoret (2) , Renée Pontikis (3) , Joelle Dubois (2, 4, 5) , Luc Morin-Allory (1) , Jean-Claude Florent (3, 6, 3)

1 ICOA - Institut de Chimie Organique et Analytique
2 ICSN - Institut de Chimie des Substances Naturelles
3 CSVB - Conception, synthèse et vectorisation de biomolécules
4 Le2i - Laboratoire Electronique, Informatique et Image [UMR6306]
5 UMR ISEM - Institut des Sciences de l'Evolution de Montpellier
6 CDC - Compartimentation et dynamique cellulaires

A series of novel combretastatin A4 analogues, in which the cis-olefinic bridge is replaced by a cyclopropyl-vinyl or a cyclopropyl-amide moiety, were synthesized and evaluated for inhibition of tubulin polymerization and antiproliferative activity. The derivative 9a with a (cis,E)-cyclopropyl-vinyl unit is the most promising compound. As expected, molecular docking of 9a has shown that only one of the cis-cyclopropyl enantiomers is a good ligand for tubulin.

Domaines: Biologie cellulaire

Nancy Ty, Julia Kaffy, Alban Arrault, Sylviane Thoret, Renée Pontikis, et al.. Synthesis and biological evaluation of cis-locked vinylogous combretastatin-A4 analogues: derivatives with a cyclopropyl-vinyl or a cyclopropyl-amide bridge.. Bioorganic and Medicinal Chemistry Letters, 2009, 19 (5), pp.1318-22. ⟨10.1016/j.bmcl.2009.01.062⟩. ⟨hal-00371153⟩