The long-term objectives of this research program are (i) to explore and develop new and efficient methodologies for the syntheses of a variety of compounds of medicinal interest and (ii) to discover and develop new and effective anticancer agents as MDR reversal agents. This research program is very interdisciplinary and has been and will be carried out in collaboration with world-leading experts in each discipline. There are three specific aims: (1) Development of efficient methods for the synthesis of enantiopure non-protein amino acids, peptidomimetics and related compounds of medicinal interest. It is essential to develop and establish efficient and reliable new synthetic methodologies in order to attack important problems in medicinal chemistry and molecular medicine. As an approach to this challenging goal, the PI will further promote our very productive research on the asymmetric synthesis of non- protein amino acids, dipeptide isosteres and related compounds. New methods applicable to combinatorial chemistry will be developed. (2) Development of new generation taxoid antitumor agents (2.1.) Determination of bioactive conformation of paclitaxel. It is extremely important to find out how paclitaxel, a powerful anticancer drug, interact with microtubules in order to stabilize it and then to inhibit the cell division. The PI is very close to reveal the microtubule-bound conformation of paclitaxel for the first time using fluorine probe of paclitaxel by means of the solid state 19FNMR analysis as well as exciton chirality CD method. (2.2.) Design and synthesis of second and third generation taxoid antitumor agents. The PI will continue to develop the second generation taxoids based on the SAR study. The PI will find out the common pharmacophore of paclitaxel, epothilones, and discodermoride based on the information obtained in the specific aim (2.1.), SAR study, and molecular modeling. Once the common pharmacophore is defined, the PI will design the third generation taxoid antitumor agents that may not have taxane structure anymore. (2.3.) Studies on the photoaffinity labeling with, the metabolism of and macrophage activation by taxoids. The PI will perform photoaffinity labeling of microtubules and P-glycoprotein as well as the metabolic study of taxoids by P-450s using strategically fluorinated taxoids that can block specific oxidation sites. The PI will also look at the ability of taxoids to activate macrophages producing NO and/or TNFalpha. (3) Development of new MDR reversal agents from baccatins. Drug resistance in cancer chemotherapy is a serious problem. In order to solve this problem, the PI will continue his successful approach to the development of MDR reversal agents based on the strategic modification of baccatins.
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