Since the beginning of recorded history, materials from living sources have been used in the treatment of human disease. Over fifty cytotoxins have been discovered from sponges, largely by screening against in vivo murine leukemia. However, little knowledge has been accumulated about extracts or metabolites that might be active against the major human solid tumors that have been resistant to chemotherapy. The goal of this study is to engage in a phyletic approach to discover new cytotoxic heterocyclic polyketides, cyclic amino acids, or ketide-amino acids from marine sponges. Collaborative arrangements with the natural products branch of the NCI and with industry will provide in vitro screens against both rapidly growing tumors of the well known P388 and KB cell lines and slow growing solid tumors such as lung, mammary, and colon cells. This proposal will uncover marine natural products with fundamentally new types of molecular structures. One focus is on sponges of the Choristida order because of our past success in discovering new cytotoxins from their membranes. Also, a search of the literature indicates their taxa will be of continuing promise. Another array of techniques will bring the unusual metabolites noted above to the forefront. Extracts will be evaluated by a combination of """"""""CTOX rating"""""""", """"""""NMR rating"""""""" and, """"""""AA rating"""""""" in respectively: cytotoxicity prescreens, 13C NMR multipulse analysis, and DAO (D-amino acid oxidase) assay. Compounds with novel structures will be completely defined by exhaustive NMR study, by computer molecular modeling, and by X-ray examination of crystals (when possible). Ionophoric properties of the larger ring heterocyclics will also be investigated. There are four components within the proposal. Project I """"""""Polyketide and ketide-amino acid cytotoxins from non-Choristid sponges"""""""" - centers around the chemistry of mycothiazole, fijianolides, and latrunculin A. Project 2 """"""""Small and medium ring heterocyclic polyketide amino acid cytotoxins from Choristid sponges"""""""" - focuses on the bengamides, bengazoles, and ketopiperazines. Project 3 """"""""Macrocyclic ketide-amino acids cytotoxins from Choristid sponges"""""""" - converges on jasplakinolide (jaspamide) and its derivatives. Project 4 """"""""New ketide-amino acid or amino acid cytotoxins from Choristid sponges - investigates new sponges obtained both by rational and random collections.
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