Crystal Structures of Taxol and Taxol Analogues

Although the mechanisms of taxol antitumor activities and toxicity are not understood at themolecular level, they must involve interactions between the drug and various receptors on athree-dimensional level. Therefore, a rational way to achieve more selective taxol analogues would beto determine the three-dimensional stereochemistry of taxol, and of taxol derivatives with differingdegrees of anticancer activity and toxicity; the structures could then be compared and the differentstereochemical features responsible for the different activities may be identifiable. To this end we haveprocured a sample of taxol and have been successful in obtaining single crystals for structuredetermination by x-ray diffraction. Taxol crystals have cell dimensions a=9.67, b=28.24, c=19.83A,and contain two independent taxol molecules plus some solvent molecules in the unit cell. They diffractto 1.05A, affording a possible 5000 independent x-ray data collectable. We shall determine thethree-dimensional stereochemistry of taxol, including the locations in space and conformations of allfunctional groups. We shall also crystallize and elucidate the structures of several taxol analogues ofknown activities; comparisons of stereochemistries will then be made to determine the stereochemicalparameters responsible for efficacy, toxicity, transport, etc. This information will be very beneficial forthe rational design of more selective taxol analogues.