NUCLEAR TARGETS FOR NATURAL PRODUCTS DRUG DISCOVERY

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The long term objective of this Laboratory Program is the identification of compounds suitable for development as antitumor agents. During the project period, objectives include: (1) utilizing yeast-based screens for DNA damaging agents to identify mechanistically unique species whose behavior suggests potential utility as antitumor agents. (2) utilizing topoisomerase I as a locus for the development of new antitumor agents by isolating additional inhibitors of topoisomerase I function, producing large numbers of structural analogues of identified inhibitors using combinatorial chemistry techniques, and developing several secondary discriminators that can be used to identify those topoisomerase I inhibitors likely to be of utility as antitumor agents. (3) obtaining more potent inhibitors of DNA polymerase beta so that it is possible to complete the testing of the hypothesis that these agents can potentiate the cytotoxic activity of activity of antitumor agents that act by creating DNA lesions, and demonstrate the ability of such inhibitors to potentiate the antitumor activity of agents such as bleomycin, esperamicin and calicheamicin (4) prioritizing the lead compounds identified by the studies outlined above and obtaining the most promising compounds in quantitities sufficient for antitumor evaluation in experimental animal models/initial preclinical development (5) enhancing our prospects for identifying novel antitumor agents by preparing additional plant extracts from plant samples already in hand.