Synthesis and NMR-driven conformational analysis of taxol analogues conformationally constrained on the C13 side chain.
Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion of a carbon linker between the 2'-carbon and the ortho-position of the 3'-phenyl ring were synthesized. Biological evaluation of these new taxoids showed that activity was dependent on the length of the linker and the configuration at C2' and C3'. Two analogues in the homo series, 9a and 24a, showed tubulin binding and cytotoxicity comparable to that of Taxol. NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution of the averaged 2-D NMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobically collapsed "nonpolar" and "polar" classes are represented by one conformation each with predicted populations of 12-15%. The five remaining conformers, however, are extended, two of which correspond to the T-conformation (47% of the total population). The latter superimpose well with the recently proposed T-Taxol binding conformer in beta-tubulin. The results provide evidence for the existence of two previously unrecognized structural features that support Taxol-like activity: (1) a reduced torsion angle between C2' and C3' and (2) an orthogonal arrangement of the mean plane through C1', C2' and the 2'-hydroxyl and the 3'-phenyl plane, the latter ring bisected by the former plane. By contrast, epimerization at 2',3' and homologation of the tether to CH2-CH2 were both detrimental for activity. The decreased activity of these analogues is apparently due to configurational and steric factors, respectively.
Barboni
L
L
Dipartimento di Scienze Chimiche, Università di Camerino, Italy. barboni@camserv.unicam.it
Lambertucci
C
C
Appendino
G
G
Vander Velde
D G
DG
Himes
R H
RH
Bombardelli
E
E
Wang
M
M
Snyder
J P
JP
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043823:Taxoids; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured
C427227:2',2''-methylenedocetaxel; C427226:2',2''-methylenepaclitaxel; D000970:Antineoplastic Agents; D043823:Taxoids; D014404:Tubulin; D017239:Paclitaxel