Preclinical development of fungal secondary metabolites and the discovery of new metabolites with cytotoxic properties

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

Abstract: Cancer is still the second leading cause of deaths worldwide and responsible for nearly 10.0 million deaths in 2020. In addition to the high morbidity and mortality rate, cancer results in a significant economic burden on the healthcare systems and countries all over the world. The discovery and development of new anticancer leads is essential with the continuous emergence of anticancer resistance. Secondary metabolites from natural resources played a major role in the discovery of chemotherapy drugs, particularly those from plant and microbial origins. Although fungi represent a valuable source of promising cytotoxic molecules, none of the fungal secondary metabolites or any of their derivatives have been successfully approved for cancer management in the clinical settings. As part of a multidisciplinary project to identify and develop anticancer leads from fungal origin, my research work involved the development of a local prolongedrelease drug delivery system of eupenifeldin, a fungal secondary metabolite with potent cytotoxic properties. This delivery system significantly reduced the reoccurrence of lung cancer in in vitro and in vivo models. In addition, various fermentation conditions were investigated to enhance the obtained yield of the two main cis-enone RALs (hypothemycin and 5Z-7-oxozeaenol) from fungal strains MSX78495 and MSX63935, and the photoactivated perylenequinones (mainly ent-shiaraiachrome A) from Shiraia-like sp. (strain MSX60519). These studies allowed for the isolation and purification of 1043 mg of hypothemycin, 760 mg of 5Z-7-oxozeaenol, and over 700 mg of ent-shiraiachrome A. In addition, the redox behavior of fungal perylenequinones were investigated and allowed for better understanding the biosynthesis of these fungal secondary metabolites. Overall, this work allowed the identification of 34 fungal secondary metabolites, of which 26 are known and eight are new.

Additional Information

Language: English
Date: 2021
Diketomorpholines, Eupenifeldin, Hypocrellin, Hypothemycin, Perylenequinones, Resorcylic acid lactones
Antineoplastic agents
Fungal metabolites

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