The primary objective of this research project is the isolation and structural elucidation of novel pharmacologically-active metabolites from marine invertebrates, with particular emphasis on the discovery of potential drugs for the treatment of cancer and AIDS. The research program involves field collection and identification of marine organisms, bioassay-directed isolation of cytotoxic, anti-mitotic and antifungal compounds, and structural elucidation of active and/or novel marine natural products. A major emphasis is placed on early dereplication of known compounds. Secondary objectives include studies of the mechanism of action of active agents, efforts to make active metabolites available for broader pharmacological screening, and attempts to correlate bioactivity with taxonomic classification and ecological parameters. Priorities for field collection are based on prior collecting experience, ecological clues, and simple field bioassays. While most cytotoxicity assays are too complex to perform in the field, some indication of biomedical potential can be obtained from simple antimicrobial assays. An assay that detects inhibition of cell division in the fertilized sea urchin egg can be performed at field stations. Our extensive collecting experience enables us to avoid specimens that have already been studied and a knowledge of sponge taxonomy allows us to concentrate on new specimens of those groups of sponges that have been reported to contain promising compounds. Our unrelated studies of the chemical ecology of marine invertebrates have enabled us to develop criteria for collection that are based on field observations. We anticipate that this research project will continue to generate new cytotoxic agents with novel chemical structures, but we recognize that the pace of discovery will be slower as more compounds are reported. We will have to place more emphasis on dereplication as the field matures. We currently have about 10 'active' extracts in hand and have a new collection of 90 temperate Indo-Pacific invertebrates to be screened. We expect to collect samples from less accessible locations as well as recollecting in familiar places. We propose to add cytotoxicity screening of crude extracts and to expand our collaborative programs to ensure the widest possible pharmacological screening for all compounds isolated.
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