CONFORMATIONAL STUDIES OF PACLITAXEL ANALOGS MODIFIED AT THE C-2' POSITION IN HYDROPHOBIC AND HYDROPHILIC SOLVENT SYSTEMS

The conformations of two paclitaxel analogs modified at the C-2' posit ion, 2'-deoxypaclitaxel and 2'-methoxypaclitaxel, were studied in hydr ophobic Emd hydrophilic solvent systems by a combination of NMR spectr oscopy, CD measurements, and molecular modeling. Both analogs have hyd rophobic and hydrophilic conformations that resemble those of paclitax el itself in the same media. Since the two have diminished biological activities in a number of bioactivity assays and the hydrogen-bonding capability of the 2'-hydroxyl group has been eliminated, we postulate that this group is involved in hydrogen bonding with tubulin and plays an important role in molecular recognition. The results of this study are in agreement with our earlier report on paclitaxel 2'-acetate, an analog in which the 2'-hydroxyl group hydrogen-bonding capacity has a lso been eliminated.