The naturally occurring diterpenoid taxol is a potent anticancer agent which shows activity in several tumor systems and has also shown excellent clinical activity against ovarian cancer and several other cancers. It is however in very short supply, currently being isolated from the bark of the western yew, Taxus brevifolia, in low overall yield. Improved methods of obtaining taxol are thus urgently needed to ensure that supplies are adequate to meet the demand for this exciting new drug. The overall goal of the proposed work is to improve the taxol supply by chemical means. In the first, short-term, part of the proposal, these improvements will be accomplished by developing ways to convert cephalomannine, a related and co-occurring compound, to taxol. In addition, methods will be developed to produce baccatin Ill in optimum yield from various Taxus species; baccatin Ill can be converted to taxol by chemistry developed by the co-principal investigator. The second, long-term, part of the proposal deals with methods to improve the taxol supply and improve taxol's medicinal value by developing more active or more accessible analogs. To this end, taxol analogs will be prepared and tested for bioactivity in the tubulin assembly assay and in other assays. The analogs to be prepared include those which differ by substitution at the C-2 or at the N-3' position of taxol, and also analogs that differ in the nature of the taxane ring system as a whole. The analog synthesis program will be guided by mechanistic hypotheses developed from previous work in the investigators' laboratories.
