NEW ANTITUMOR & ANTIFUNGAL NATURAL PRODUCTS FROM FUNGI

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Many useful drugs have been discovered through studies of microbial natural products. However, there are a number of fungal subgroups that have not been widely studied for secondary metabolite production. Furthermore, certain aspects of the ecology and life-cycles of many of these fungi specifically suggest that they should be targeted for exploration in the search for new biologically active natural products. Antagonism between species of naturally-competing fungi has been the subject of numerous literature reports. Compounds responsible for such effects are essentially natural antifungal agents, which may also exhibit other useful bioactivities. Other fungi occupy unique nutritional environments, suggesting that they may possess metabolic adaptations that differ from more common fungi. Yet another group of fungi produce large physiological structures called sclerotia that are vital to the survival of the organism, and there is significant evidence that many of these sclerotia contain unique bioactive secondary metabolites that deter feeding by fungivorous insects. Our interests lie with three subgroups of fungi that exhibit such characteristics: coprophilous, marine/aquatic, and sclerotium-forum fungi. We propose that these three types of fungi comprise a potentially valuable source of new natural products with pharmacological activity. Therefore, we intend to undertake studies of the secondary metabolites of these three fungi subgroups in search of novel compounds with antifungal, antitumor, antiviral, and other potentially useful bioactivities. Our approach to this research is largely non-random, since it is based on the application of literature evidence, ecological rationale, and taxonomic relationships. Fungal species will be chosen for study on the basis of literature reports of antagonistic effects toward competitors, late occurrence in fungal successions, occurrence in marine environments, sclerotium-forming ability, and taxonomic relationship to fungi that have already yielded bioactive agents in our preliminary studies. Fresh isolates of fungi species and sample of fungi sclerotia will be obtained through collaborative arrangements with experts in the fields of mycology and fungal taxonomy. Prescreens of culture filtrates, extracts, chromatographic fractions, and purified metabolites for antifungal, antibiotic, and potential antitumor activities will be conducted in our laboratory, and a battery of 25 additional screens (antitumor, antiviral, antifungal, immunomodulatory, etc.) will be conducted by a cooperating pharmaceutical company. State-of-the art chromatographic and spectroscopic techniques will be used in the isolation and structure determination of active metabolites. Initial results indicate that a high percentage of the fungi we have selected thus far produce extracts that exhibit activity, and we have isolated and characterized over twenty new biologically active natural products using this approach. Through our studies in this area, we propose to explore the natural products chemistry of these fungi subgroups, while evaluating the potential of an ecologically-based approach to the discovery of novel bioactive agents.