This research has been designed to discover new paradigms of marine sponge-derived natural products chemistry. A long term focus is to isolate and study novel alkaloids and oxygen containing compounds. A further emphasis is to obtain compounds active against solid tumor cancers, for which there are few effective drugs.
The specific aims are: (a) To discover new sponge derived anticancer agent candidates using the WSU in vitro disk-diffusion soft-agar-colony- formation-assay which detects agents with """"""""cellular selectivity"""""""" for solid tumors by employing leukemia (L1210) cells, murine and human solid tumors (that are insensitive to conventional anticancer agents) and normal cells. (b)To continue the study of potent cytotoxic or antitumor active alkaloids or oxygen heterocycles discovered by our lab during prior research. (c) To emphasize under-explored sponge taxonomic orders such as the Choristida, Dendroceratida, Haplosclerida, Hadromerida, Lithistida, and Pioecilosclerida. (d) To explore sponge taxa which might have a broadened scope of nail products because of the presence of symbionts including photosynthetic microorganisms. (e) To efficiently purify solid tumor active cytotoxins (with emphasis on the cancers listed above) from active crude extracts by in vitro bioassay-guided isolation (f) To complete the structure elucidation of active compounds. (g)To develop new anticancer leads for future clinical trials by using in vivo evaluation in the mouse models at WSU to examine the in vitro active compounds once they have been characterized and isolated in sufficient amounts, with the highest priority given to compounds where selectivity is detected against a human tumor cell. Nonspecific cytotoxic agents have not been broadly useful in treating the common cancers noted above. Lead compounds, as potential solid tumor active agents, will be identified by a multistage process. Indo-Pacific sponges will be obtained from remote, relatively unexplored sites. Extracts and compounds will also be screened in the soft agar disk diffusion assays provided by Drs. Corbett and Valeriote at Wayne State University (WSU), and purified compounds will be evaluated, as appropriate, in the National Cancer Institute - Developmental Therapeutics Program (Na-DTP) in vitro 60-cell line panel. """"""""Benchtop assays"""""""" are being developed at the University of California, Santa Cruz (UCSC) to speed-up the isolation of compounds from extracts active in the WSU assays. These will examine crude extracts for the ability to cause brine shrimp lethality, or to effect recombinant yeasts via mechanisms such as DNA damaging or cytoskeletal disruption. Structure determinations will emphasize contemporary NMR techniques applied in a concise fashion. Compounds active in the primary screens will be examined in secondary screens to test for selectivity, potency, mechanism of action and in vivo effects.
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