Document Type

Dissertation

Date of Degree

Spring 2017

Access Restrictions

Access restricted until 07/13/2018

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

James B. Gloer

Abstract

Fungi are renowned for their ability to produce a wide array of secondary metabolites with unique and diverse structures. Some of these compounds possess important biological activities, which make them useful agents in medicine for treatment of various diseases or in agriculture for control/elimination of pests and pathogens of economically important crops. However, there still remains great untapped potential in the fungal kingdom as only about 100,000 species have been formally described out of approximately 1.5 million species that exist. Many fungi are fairly ubiquitous in soil or other common substrates, while others belong to more specific niche groups and are categorized as marine, freshwater, endophytic, fungicolous/mycoparasitic, or coprophilous, or with other descriptors, based on their ecological origin. Some of these niche groups, such as marine and endophytic fungi, have been commonly studied in recent years, while others, including coprophilous fungi, remain relatively underexplored. Studies on these underexplored groups could potentially yield more new and structurally unique compounds with important biological activities. Different research groups employ different tactics in targeting fungi for chemical studies. The research in our group incorporates a strategy based on ecological origin in targeting fungi for investigation, and this approach has proven to be successful over the years. The work described in this thesis involves studies of fungicolous and coprophilous fungi as potential sources of novel biologically active metabolites.

Chemical investigation of 27 fungicolous isolates collectively yielded three new compounds and 20 previously known compounds. The known compounds that were encountered belong to a variety of different compound classes and most of them have been reported to exhibit biological activities including antifungal, antibacterial, and cytotoxic effects. The new compounds isolated included two polyketide metabolites, hynapenes D and E, which were found to be new analogues of the previously reported hynapenes A-C. Hynapene D possesses an oxygenated methylene unit absent in other members of this class, while hyanapene E is an isomer of hynapene A.

Studies on fermentation extracts of 38 coprophilous fungal isolates yielded a total of 11 new compounds and 26 known compounds. Hypocoprins A-C, isolated from Hypocopra rostrata, are the first sesquiterpenoids with fused cyclodecene and cyclopropane ring systems, and the first compounds of any kind with this ring system to be reported from a fungal source. The flutimide-producing fungus Delitschia confertaspora yielded delicoferones A and B, which possess an unprecedented skeleton with three benzene rings linked via two ketone carbonyl groups. This organism also produced delicoxazone, a compound containing two para-disubstituted aromatic rings linked via a 1,3-oxazine-4-one unit, which is the first compound from a fungal source to contain this structural feature. A fourth compound isolated from this organism, was found to be an analogue of the unusual compound fimetarone A, and was named fimetarone B. Studies of an unidentified Cercophora species afforded three new sambutoxin derivatives (cercophorones A-C), out of which, cercophorone C was found to exhibit significant activity against the human pathogenic fungus Cryptococcus neoformans, and weak activity against Candida albicans, with MIC values of 6.4 and 12.8 µg/mL, respectively.

The compounds encountered in this work were isolated using a variety of chromatographic techniques including silica gel column chromatography and RP-HPLC. The structures of these compounds were determined mainly by analysis of NMR and MS data, although in some instances chemical derivatizations were also employed. Where applicable, relative configurations were determined based on NOESY data and/or coupling constants, and absolute configurations were assigned by application of Mosher’s method. Details of the isolation and structure elucidation of the new compounds described above are presented in Chapters 2-6 of this thesis.

Pages

xvii, 208 pages

Bibliography

Includes bibliographical references (pages 193-208).

Copyright

Copyright © 2017 Dinith Rangana Jayanetti

Available for download on Friday, July 13, 2018

Included in

Chemistry Commons

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