CRYSTAL STRUCTURES OF TAXOL AND TAXOL ANALOGUES

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Although the mechanisms of taxol antitumor activities and toxicity are not understood at the molecular level, they must involve interactions between the drug and various receptors on a three-dimensional level. Therefore, a rational way to achieve more selective taxol analogues would be to determine the three-dimensional stereochemistry of taxol, and of taxol derivatives with differing degrees of anticancer activity and toxicity; the structures could then be compared and the different stereochemical features responsible for the different activities may be identifiable. To this end we have procured a sample of taxol and have been successful in obtaining single crystals for structure determination 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 diffract to 1.05A, affording a possible 5000 independent x-ray data collectable. We shall determine the three- dimensional stereochemistry of taxol, including the locations in space and conformations of all functional groups. We shall also crystallize and elucidate the structures of several taxol analogues of known activities; comparisons of stereochemistries will then be made to determine the stereochemical parameters responsible for efficacy, toxicity, transport, etc. This information will be very beneficial for the rational design of more selective taxol analogues.