Graduation Year
2024
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Tyler Johnson, PhD
Second Reader
Ryo Higuchi-Sanabria
Abstract
The Indo-Pacific Marine sponge, Cacospongia mycofijiensis, continues to be a prolific source of bioactive compounds that have made significant advancements to biomedical research. Secondary metabolites isolated from this marine sponge exhibit unique bioactivity, targeting a variety of distinct biological pathways. One such chemotype is the potent mitochondria complex 1 (MC1) inhibitors (+)-(5Z)-(8S)-(14Z)-mycothiazole (1) and (-)-(5Z)-(8R)-(14Z)-mycothiazole (2) routinely isolated from Vanuatu and Tongan specimens of C. mycofijiensis, respectively. Small molecule inhibitors of the electron transport chain, such as 1 and 2, hold significant promise to function as chemical probes—over genetic manipulation approaches—for studying the relationship between mitochondrial stress and aging, as they overcome a major limitation of genetic approaches, which is a serious challenge to apply in genetic interventions involving clinical applications. In the course of scaling up the isolation of 1 to semi-synthesize (-)-(5Z)-(8S)-8-O-acetyl-(14Z)-mycothiazole (3) for ongoing preclinical development and the first aging study utilizing this chemotype, a new diastereomer, (-)-(5E)-(8R)-(14Z)-mycothiazole (4), was discovered. The structure of 4 was elucidated using HRMS and NMR, with its optical rotation value compared to that of 2. The IC50 of 4 in pancreatic (PANC-1) and liver (HepG2) cancer cell lines was determined to be 111.6 and 115.0 nM, respectively. Evaluation of 4 in Caenorhabditis elegans revealed a similar oxygen consumption rate (OCR) of 4 compared to 1 and 3, and all compounds (1, 3-4) significantly increased lifespan. Notably, the Z orientation at ∆5-6 of 1 is crucial for its picomolar cytotoxicity but not for mitochondrial inhibition. These findings underscore the importance for the stereochemistry of the diene-ol system of 1 in terms of its bioactivity, paving the way for further medicinal chemistry exploration of mycothiazole analogs in oncology, mitochondrial research, and aging studies.
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