| Abstract
| - Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion ofa carbon linker between the 2‘-carbon and the ortho-position of the 3‘-phenyl ring weresynthesized. Biological evaluation of these new taxoids showed that activity was dependenton the length of the linker and the configuration at C2‘ and C3‘. Two analogues in the homoseries, 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-DNMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobicallycollapsed “nonpolar” and “polar” classes are represented by one conformation each with predictedpopulations of 12−15%. The five remaining conformers, however, are extended, two of whichcorrespond to the T-conformation (47% of the total population). The latter superimpose wellwith the recently proposed T-Taxol binding conformer in β-tubulin. The results provide evidencefor the existence of two previously unrecognized structural features that support Taxol-likeactivity: (1) a reduced torsion angle between C2‘ and C3‘ and (2) an orthogonal arrangementof the mean plane through C1‘, C2‘ and the 2‘-hydroxyl and the 3‘-phenyl plane, the latterring bisected by the former plane. By contrast, epimerization at 2‘,3‘ and homologation of thetether to CH2−CH2 were both detrimental for activity. The decreased activity of these analoguesis apparently due to configurational and steric factors, respectively.
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