Precursor directed biosynthesis for the discovery of ‘non-natural’ natural products in fungi

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Boukar Koumba Sene Faye (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Nicholas Oberlies

Abstract: Verticillins are a class of dimeric epipolythiodioxopiperazine alkaloids that are known to have IC50 values of 10 nM or less in various human cancer cell lines This biological activity makes them potential candidates in the search of new anticancer drugs. However, further studies are hindered by limited supply when isolating verticillin class secondary metabolites from fungal sources. Thus, the search for fungal strains that produce these secondary metabolites at equal or greater abundances than the fungal strain currently being used in our lab, MSX59553, is necessary. This study revealed MSX59549 as a fungal strain of interest due to its production of verticillin A and verticillin H in higher abundances than MSX59553. Three additional fungal strains, MSX39480, MSX43578 and MSX60138, were also found to produce more verticillin H than MSX59553. These results lead to optimizing the isolation of verticillins for use in future chemical and pharmacological studies. The generation of fluorinated verticillin derivatives has been achieved using precursor directed biosynthesis to incorporate 5-fluorotryptophan into the verticillin structures while retaining the potent biological activity. Further precursor directed biosynthesis experiments using 5-hydroxytryptophan, 5-chlorotryptophan and 5-bromotryptophan lead to the production of 9-hydroxyverticillin A and 9-chloroverticllin A. Further studies involving the isolation of these verticillin derivatives and semisynthetic modification via cross coupling reactions may improve pharmacological properties within the verticillin class.

Additional Information

Language: English
Date: 2020
Cancer, Epipolythiodioxopiperazine alkaloids, Fungi, Natural products, Verticillin
Fungal metabolites
Metabolism, Secondary
Antineoplastic agents

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