There is considerable interest in the development of more selective anti- tumor agents as well as chemo-therapeutics for multi-drug resistant cancers. Conventional approaches have focused on therapeutic agents which selectively The acetogenins are a new class of naturally occurring agents which has shown potent activity against a number of cancerous cell lines, excellent selectivity in certain cases, and promising efficacy results with xenografts on athymic mice. In another direction, Photo Dynamic Therapy (PDT) has emerged as a promising treatment. However, there are many problems with the present PDT technology (based on porphyrins), including poor selectivity, poor solubility, and the dosaging is complicated by the presence of a variety of compounds such as multimers. In connection with the design of more effective PDT and traditional anti- tumor agents, synthetic methods will be developed for a variety of porphyrins (Type 1), and analogues of the THF-acetogenins (Type II). A methodology targeting a set of porphyrin-acetogenin conjugate molecules (Type III) will also be developed. Type II targets have been designed to utilize the structural features of the acetogenins to facilitate delivery and impact selectivity to PDT agents. new porphyrins will be discovered via a combinatorial chemistry approach, while the strategy for the acetogenins will be a divergent one centering on the initial synthesis of versatile relay compounds. In addition to the specific research directions, this proposal is aimed at the development of the scientific infrastructure at Hunter College for the education and to training of the undergraduate and graduate students. This project will also serve to broaden the research interests of the faculty and to provide the impetus for initiatives in multi-disciplinary research. These goals will be achieved through the very theme of this project, the necessary collaboration between the Drain and Mootoo groups, and the formal workshops and special topic courses which are part of the overall program for Molecular Mechanisms of Disease (MMD).
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