The overall goal is to isolate and identify new marine natural products as leads for cancer chemotherapy. this will be approached by the use of assays which assess biochemical differences between tumor cells and their normal counterparts. There are three specific aims. (a) To demonstrate that natural products which inhibit specific biochemical targets (including oncogene products, signal transducers, enzymes which impact tumor invasion and metastasis, and mediators of multidrug resistance) will also exhibit antitumor activity. (b) To confirm that the use of such target directed assays will minimize the discovery of agents possessing already known mechanisms. (c) To will provide anticancer drug leads from marine organisms that are structurally different from those obtained from terrestrial sources. These objectives will be achieved by the unique union of natural products chemistry and biochemistry assays outlined in this proposal. A screening schedule will be implemented that provides a rational network to discover activity in crude extracts, to guide isolation of active principles, and to provide adequate quantities of pure active compounds for in vivo follow-up testing. Extracts of selected marine invertebrates (especially tropical sponges and tunicates with photosynthetic symbionts), collected cyanobacteria, cultured microalgae (cyanobacteria, cryptophyta, and chrysophyta), and cultured anaerobic bacteria and fungi will be prepared and tested in the biochemical prescreens. Active leads will be tested further in whole cells, and then in animal models. Careful consideration has been given to the choice of taxa to be used as sources of natural products in order to maximize the discovery of interesting, active substances. Sponges and tunicates are important because of their history of yielding novel bioactive compounds. The collectable and culturable microorganisms are promising sources of bioactive substances but have not been explored to a significant extent. The culturable organisms also represent a renewable source of active compounds. The natural products will be characterized by such techniques as multi-dimensional NMR, soft ionization mass spectrometry, molecular mechanics, and x-ray diffraction. The NCNPDDG participants (as listed below) represent different institutions and distinct scientific disciplines: Cancer Biology (Slate/Ringold), Organic Chemistry (Schmitz), Pharmaceutical Chemistry (Gerwick), and Bioorganic Chemistry (Crews).
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