Paclitaxel conformation, differences

Strong support for the conformer C can be found in its close resemblance to a proposed solution structure of a water-soluble paclitaxel analogue, paclitaxel-7-MPA (MPA = iV-methylpyridinium acetate),90 in which the H2 -C2 -C3 -H3 torsion angle of the /V-phenylisoserine moiety is 127°, which is only a few degrees different from the value for the conformer C. 

After the first photoaffinity labelling studies, which were the first methods used to define the paclitaxel binding site on tubulin, and indeed allowed identification of different amino acids of p-tubulin as putative parts of the binding site [51], the initial efforts to correlate activity (or binding) with the solid state, solution or modelled conformations of MSA in their free states led to the first pharmacophore proposals... 

These interpretations prompted many organic chemists to prepare synthetic analogues, bridging different regions of the paclitaxel molecule, aimed at locking or at least favouring the putative bioactive conformation of paclitaxel on tubulin... 

Further refinement of the electron crystallographic structure of tubulin-paclitaxel at 3.5A resolution delivered a similar result. Nevertheless, the T-Taxol model has not been completely accepted as the actual bioactive conformation [78], It is evident that the low 3.5-3.7A resolution of the complex limits the precision of the resulting model. In addition, the Zn2+-stabilized tubulin preparation employed in the electron crystallographic study involves antiparallel protofilaments organized in sheets, which strongly differ from genuine microtubules. Consequently, concern has been expressed that the sheets may not be representative of cellular microtubules and that sheet-bound paclitaxel geometry may differ from its bioactive form in microtubules. 

The extension of the C-13 side chain to its homologated one furnished poorly active paclitaxel and docetaxel analogs in tubulin assembly assay. The authors assumed that the poor activity of the analogs may have originated from their different conformations from that of paclitaxel in water. 

Steric hindrance, that is, the introduction of (5)-Me to C-2, while 2 (/ )-OH is retained, makes a positive contribution to the antimmor activity as well as to the tubulin binding ability. This result may have come from the reduced rotation of the side chain, which thus enhances the ratios of bioactive conformers in all con-formers. The preparation of 2 -Me analog was usually undertaken by (3-lactam approach, in which 3-keto-(3-lactam was attacked by a nucleophile to yield stereo-selectively 3-methyl-3-OH (equivalent to the 2 position in paclitaxel) (3-lactam ready for attachment to baccatin core stmcmres. Battaglia et al. prepared a series of 2 (5)-Me of paclitaxel analogs from 10-DAB and 14(3-OH-10-DAB with different C-3 and 3 -A substitutents, and all compounds 6a-e are comparable with or more active than paclitaxel toward A2780 human lung carcinoma in vitro. °... 

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