Taxol, isolated from the stem bark of taxus brevifolia is currently considered the most exciting lead in cancer chemotherapy, possessing excellent antitumor activity against several forms of cancer. Taxol is currently in phase II clinical trial in the United States. Unfortunately, taxol is available only in small quantities from natural sources, which are threatened by extinction, should taxol prove to be effective in cancer chemotherapy. A semisynthetic approach toward taxol can be achieved through the utilization of 10-deacetyl baccatin III, a more readily available taxol related natural product. To achieve the synthesis of taxol, 10-deacetyl baccatin III has to be linked to (2'R, 3'S)-3-phenylisoserine. This research proposal describes now a highly enantioselective approach toward (2'R, 3'S)-3-phenylisoserine in two steps from readily available starting materials; a major improvement over previously reported methods for its synthesis. The key reaction is an enolate imine condensation to form beta-lactams, which can then be hydrolyzed to produce the desired 3- phenylisoserine. Since 3-phenylisoserine possesses two chiral centers, we will synthesize the four possible taxol-stereoisomers and evaluate the influence of the stereochemistry of the 3-phenylisoserine side chain on the biological activity of taxol. The proposed methodology for the synthesis of 3-phenylisoserines from beta-lactams allows flexibility with respect to the synthesis of taxol analogues. Derivatives with different substituents at the phenyl groups of the C-13 taxol side chain will be synthesized with the goal to find the substitution pattern with optimal biological activity. We will also utilize our newly developed method to synthesize derivatives of taxol with increased water solubility. Additionally, some bioisosters of taxol will be synthesized. All of the newly synthesized compounds will be tested in the microtubule assembly test and against B-16 melanoma cell growth. Promising taxol derivatives will be evaluated further, and also provided to the NCI.
| Georg, G I; Cheruvallath, Z S; Himes, R H et al. (1992) Synthesis of biologically active taxol analogues with modified phenylisoserine side chains. J Med Chem 35:4230-7 |
