TOUR DE PACLITAXEL - BIOCATALYSIS FOR SEMISYNTHESIS

In collaboration with the National Cancer Institute, Bristol-Myers Squ ibb has developed paclitaxel for treatment of various cancers; it has been approved by the Food and Drug Administration for the treatment of ovarian and metastatic breast cancer. Originally paclitaxel was isola ted and purified from the bark of Pacific yew trees. This source of pa clitaxel was considered to be economically and ecologically unsuitable as it required the destruction of the yew trees. This review article describes alternate methods for the production of paclitaxel, specific ally, a semisynthetic approach and the application of biocatalysis in enabling the semisynthesis of paclitaxel. Three novel enzymes were dis covered in our laboratory that converted the variety of taxanes to a s ingle molecule, namely 10-deacetylbaccatin III (paclitaxel without C-1 3 side chain and C-10 acetate), a precursor for paclitaxel semisynthes is. These enzymes are C-13 taxolase (catalyzes the cleavage of C-13 si de chain of various taxanes), C-10 deacetylase (catalyzes the cleavage of C-10 acetate of various taxanes), and C-7 xylosidase (catalyzes th e cleavage of C-7 xylose from various xylosyltaxanes). Using a biocata lytic approach, paclitaxel and a variety of taxane in extracts of a va riety of Taxus cultivars were converted to a 10-deacetylbaccatin III. The concentration of 10-deacetylbaccatin III was increased by 5.5- to 24-fold in the extracts treated with the enzymes, depending upon the t ype of Taxus cultivars used. Biocatalytic processes have also been des cribed for the preparation of C-13 paclitaxel side chain synthons. The chemical coupling of 10-deacetylbaccatin III or baccatin III to C-13 paclitaxel side chain has been summarized to prepare paclitaxel by sem isynthesis.