STRUCTURAL AND CONFORMATIONAL STUDIES ON TAXOIDS M. Milanesio⁺ G. Appendino*P. Ugliengo⁺ and D. Viterbo^{+ +}Dip. di Chimica IFM and *Dip. di Scienza e Tecnologia del Farmaco, Torino, Italy.

Paclitaxel (Taxol[[diamond]]) and some related molecules are important antitumor drugs, currently used for the treatment of ovarian and breast cancer. Structure-activity studies have shown that the terpenoid core behaves as a scaffold, keeping the aminoacidic side chain in the right place for the binding to the receptor surface. Because of the chain flexibility, it is not clear which conformation is recognized by the tubuline receptor and the present study is addressed to clarify this problem.

We have carried out the crystal structure analysis of baccatin III, corresponding to the terpenoid core of Paclitaxel, and of three other naturally occurring Taxoids. The conformation of the terpenoid core is very similar in all these compounds.

At the same time we have undertaken a theoretical conformational study on the aminoacidic side chain in order to assess the importance of intra- and intermolecular hydrogen bonds in dictating the most stable conformers in polar and apolar media. The possible conformations of the main skeleton of the side chain were taken from the crystal structures of Taxotere and Paclitaxel and from NMR results and molecular mechanics calculations. On these conformations we have carried out Hartree-Fock ab-initio calculations [6-31G(d,p) basis set and full geometry optimization] using a simplified model of the chain. The results of this analysis show that: i) the gas-phase minimum energy conformation corresponds to that found in Taxotere while all other conformers have energy at least 2.0 kcal/mole higher; ii) when simulating a polar solvent by the continuum Onsager method, there are five different conformations differing by less than 1.0 kcal/mole, suggesting their possible coexistence in solution in keeping with the NMR results; iii) among these five conformations one is similar to that found in the crystal structure of Paclitaxel.