In spite of significant shortcomings among existing clinical antifungal agents, the rate of development of new therapeutics has been sluggish, and the mortality rate caused by fungal diseases has remained almost unchanged. Natural products have provided useful templates for the development of several of the most important therapeutic antifungal agents. In particular, fungi have been rich sources of antifungal natural products, and many fungal species remain chemically underexplored. Our research program has focused on fungicolous and coprophilous fungal niche groups. These types of fungi often show antagonistic effects toward host or competitor fungi—a phenomenon hypothesized to be associated in part with the production of antifungal metabolites. Earlier results reported from our research program have shown that studies of such fungi can be effective approaches to the discovery of new bioactive natural products, including antifungal agents.
During our continued efforts to discover new antifungal and antiinsectan natural products, diverse fungal metabolites were obtained from complex fermentation extracts by use of various chromatographic methods. In addition to previously known compounds and simple analogues thereof, structurally interesting new metabolites were encountered. Those isolated from fungicolous fungi include ten new caryophyllene-type sesquiterpenoids from a Pestalotiopsis sp., three of which contain previously undescribed ring systems or new skeletons. The remainder are oxidized analogues of punctaporonins. Seven new polyketide-derived metabolites were obtained from another Pestalotiopsis isolate, in this case, P. disseminata, and two unusual ring systems were identified. A distinctive biosynthetic pathway was proposed for these seven polyketides. Members of another class of polyketides (pyrenocines), which contain pyrone or thiopyran units, were encountered from Penicillium paxilli. One of the three new pyrenocine analogues obtained contains an adenine unit—a rare feature among fungal secondary metabolites. Chemical investigation of another Penicillium sp., P. lanosum, afforded a new fumiquinazoline analogue, as well as a compound previously described in a thesis of a member of our research group. In work described here, the original stereochemical assignment was revised, and the compound was renamed as lanosindole. Metabolites isolated from this fungicolous Penicillium isolate have amino acid origins in common, and two of them showed antiinsectan activity. Seven new polyketide alcohols were obtained from the coprophilous fungus Podospora appendiculata. Two of them contain a tetrahydropyran unit and three are acyclic, differentiating them from other known members of this class. Finally, funiculosin B, an antifungal metabolite of mixed biogenetic origin containing a rare tetrahydroxycyclopentanyl moiety, was isolated from a flower-colonizing isolate of Capnodium sp.
The structures of the compounds described above were determined mainly by analysis of NMR and MS data. Synthetic modification, X-ray crystallographic analysis, and ECD data analysis in conjunction with molecular modeling were applied to their stereochemical assignments. The results described in this thesis indicate that fungicolous and coprophilous fungi are prolific producers of new natural products, some of which display activity in assays of medical and agricultural relevance. Although most of the new compounds described here were inactive against pathogenic fungi, the rich diversity of chemistry encountered suggests potential for this ecology-based approach in the discovery of new bioactive natural products.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-7431 |
| Date | 15 December 2015 |
| Creators | Hwang, In Hyun |
| Contributors | Gloer, James B. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright © 2015 In Hyun Hwang |
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