Studies on epipolythiodioxopiperazine alkaloids

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Chiraz Soumia M. Amrine (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Nicholas Oberlies

Abstract: Natural products research remains a fertile source for drug discovery due to the complexity, chemical diversity and biological activity of compounds discovered from nature. Verticillins are members of the epipolythiodioxopiperazine (ETP) alkaloid class of fungal metabolites and are known as potent cytotoxic agents, some with IC50 values of less than 10 nM. Studies showed that verticillin A has activity as a selective histone methyl transferases inhibitor with important anticancer properties. However, several challenges slowed the further development of this class of compounds. The goals of this project strived to address such challenges in the development of the ETP alkaloids in three ways: (1) enhancing the production of verticillins, (2) identifying and isolating new analogues of the verticillins, and (3) developing a targeted delivery approach for the verticillins. Aim 1 was achieved by analyzing different fungal strains under a suite of fermentation conditions. These studies were facilitated by the use of the droplet-liquid microjunction-surface sampling probe (droplet probe) coupled with UHPLC–PDA–HRMS/MS, which enables chemical analysis in situ directly from the surface of the cultures. These experiments showed that the production of verticillins was greatly affected by growth conditions. Using these technologies to select the best among the tested growth conditions, the production of the verticillin analogues was increased in laboratory scale fermentation. Aim 2 was achieved via using a precursor-directed biosynthesis approach that was monitored in situ via droplet probe. To characterize the generated series of “non-natural natural products”, a suite of NMR and mass spectrometry data were collected. This approach yielded novel compounds that would be difficult to generate via synthesis. Furthermore, and in a collaborative manner, the generation of new analogues was also achieved via semisynthetic approaches that generated ester, carbonate, sulfonate and carbamate derivatives of the verticillins. This synthetic process was characterized by the use of 1H NMR to monitor the various reactions. Aim 3 was achieved by encapsulating verticillin A into an expansile nanoparticles (verticillin A-eNP). This delivery system was used to circumvent two imperative issues of the drug administration of verticillins. First, the verticillin A-eNP was used to shield healthy cells, by targeting cancerous cells, as it permits the retention of the eNPs inside the cancer cells and the continuous release of the drug in their acidic environment Secondly, the verticillin A-eNP enhanced the solubility of the poorly soluble verticillins, facilitating a more straight forward approach to their delivery and testing in vivo.

Additional Information

Language: English
Date: 2019
Fungal metabolites

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