The project aim is to contribute to the search of new cancer chemotherapy agents. This research will discover and study novel marine sponge-derived compounds possessing in vitro potency against slow growing tumor cells. Cancer assay models are provided by two collaborators, Dr. Jake Clement of Abbott Laboratories, and the National Cancer Treatment (NCI-DCT) group, coordinated by Dr. Ven Narayanan. The long term goals are: (a) to uncover new structural concepts for cytotoxic active natural products, (b) to employ a concise approach which involves rapid in vitro assays as a tool to screen extracts from meagerly explored marine sponge families, (c) to isolate cytotoxic principles from sponge taxa predicted as being a source of natural products biosynthesized by symobionts including photosynthetic microogranisms or heterotrophic bacteria, (d) to efficiently elucidate the structures of active compounds, (e) to pursue and modify potent cytotoxic alkaloids discovered during the investigators prior research, and (f) to forward the most selective in vitro active natural product or semisynthetic derivatives to the collaborators for in vivo assay follow-up. An innovative experimental plan is in place to guide this project. Special emphasis is being devoted to taxa from two sponge orders, Choristida and Poecilosclerida. The investigator's work to date has shown that sponges of the former order can be considered as a prime source for novel cytotoxic alkaloids. The literature provides justification for the belief that sponges of the latter order are a source of diverse heterocyclics possibly derived from symbiotic heterotrophic microorganisms. Selected genera from other sponge orders, which may possess photosynthetic symbionts such as cyanobacteria, are targeted for investigation because they should yield new secondary metabolites. Compounds with novel structures will be completely defined by exhaustive NMR study, computer molecular modeling, and X-ray examination when suitable crystals can be grown. A part of this project will be the continuation of studies on sponge products possessing desirable cytotoxicities. This will involve cytotoxic alkaloids from as many as eleven structural classes discovered during the investigator's prior research. Corresponding attention will be given to isolating analogs and preparing semisynthetic derivatives of these active lead compounds.
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