One of the objectives of the proposed research is to develop and establish efficient and reliable new methodologies for the synthesis of various non-protein amino acids and related compounds of medicinal interest with perfect control of stereochemistry. Such methodologies are very beneficial for (i) the investigation of the biological functions of non-protein amino acids and related compounds which cannot be obtained in sufficient quantity by isolation from natural sources, and (ii) the development of enzyme inhibitors, antitumor agents, antibiotics, and peptide hormones. As an approach to this challenging goal, we will further promote our very productive research on the asymmetric organic transformations of enantiomerically pure N-acyl-Beta-lactams. Those non- protein amino acids and their derivatives, thus obtained, will furnish components of enzyme inhibitors, antitumor agents, antibiotics, plant metabolites, and peptide hormone analogs, carbohydrates, chiral macrocycles, and chiral ligands for reagents and catalysts for asymmetric synthesis. The other objective of the proposed research is to discover and develop new and potent antitumor agents, especially for breast and lung cancers, through systematic modifications of the taxol skeleton and the structure- activity relationship studies. These new taxoid antitumor agents various tumor types different from those of taxol and taxotere. We will focus on new taxoid antitumor agents derived from a new taxane, 14-hydroxy-10- deacetylbaccatin III (140DAB), isolated from Taxus Wallichiana Zucc (Himalayan yew). One of the serious drawbacks of taxol is its poor water solubility, which causes practical problems in its formulation, e.g., a special vehicle is required which has its own side effects, and the maximum dose may be limited by its solubility. Taxotere has somewhat improved solubility and thus better pharmacological properties than taxol, but this antitumor agent still has other undesirable side effects. Because of an extra hydroxyl group at the C-14 position, 14-OH-DAB has proven to possess much higher water solubility than the usual 10- deacetylbaccatin III (DAB) which is currently used for the production of taxol and taxotere. Therefore, the new antitumor taxoids derived from 14-OH-DAB are expected to have substantially improved water solubility and pharmacological properties as therapeutic agents. These improved pharmacological properties may well be related to the modification of undesired toxicity and unique activity spectra against different cancer types and multi drug resistance. Antitumor activity of these new analogs will be evaluated through ongoing collaboration with an oncology laboratory.
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