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Dubois, J ; Guenard, D ; Gueritte-Voegelein, F ; Guerira, N ; Potier, P ; Gillet, B ; Beloeil, JC

Conformation of taxotere(r) and analogs determined by NMR-spectroscopy and molecular modeling studies

Tetrahedron 49 (30) 6533-6544

par Administrateur - publié le

Abstract :

Taxol 1 and Taxotere(R) 2 are antitumor compounds interacting with tubulin proteins. In order to find the best conformational fit to the receptor site, the structures of taxotere and twelve analogues showing various in vitro biological activity on tubulin, have been investigated by H-1 NMR spectroscopy and molecular modeling studies. These structures were compared to that of Taxotere(R) 2 obtained by X-ray analysis. The results obtained from these studies suggest that the most active 2R,3’S compounds possess a conformation in which the benzoate group at C-2 holds the side chain in a defined position due Lo hydrophobic interactions between this group and the N-amido or N-carbonyloxy group at C-3’. This situation together with the presence of hydrogen bonding between 2’OH -3’NH and 2’OH-1’C=O gives rise to a specific orientation of the hydroxyl and phenyl groups at C-2’ and C-3’. On the other hand, the 2’S,3’R isomers which display low in vitro biological activity (ie : on tubulin), such as isotaxotere 8, possess a different conformation with no hydrophobic interactions between the side chain and the taxan skeleton.