Graduation Year
2025
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Patti Culross, MD, MPH
First Reader
Tyler Johnson, PhD
Second Reader
Kenneth Frost, PhD
Abstract
The mycothiazole chemotype (1) from the marine sponge Cacospongia mycofijiensis is a mitochondrial complex I inhibitor that has lifespan extending properties in C. elegans aging models. Its di-ene-8-ol residue appears essential for its biological activity. Unfortunately, the di-ene-8-ol residue of 1 is also responsible for the lability of 1 which has a shelf life of ≤ 6 weeks. To address this, we sought to make new semi-synthetic analogs of 1 that we believed would be more stable than the natural product. In this study, the structures of these new analogs were elucidated using NMR, HRMS, and optical rotation, and lifespan assays were carried out to determine their effects on the aging process. Our results confirm the generation of two new diastereomers devoid of the diene system that feature hydroxyl and methyl group substituents on position C-4. Specifically, the structures have been identified as 4,4 hydroxy-methyl-mycothiazole (3a and 3b). Both compounds demonstrated a shortened shelf life of < 4 weeks versus natural 1 (< 6 weeks). An in vivo evaluation of 3a and 3b indicated that both compounds do not extend the lifespan of the model organism C. elegans in comparison to compound 1, although compound 3b did reduce mitochondrial respiration. These results indicate the diene system of 1 is required for its life extension properties. Future structure activity relationship (SAR) studies with this chemotype may benefit from semi-synthetic modifications of 1 to identify analogs that serve as chemical probes to study the aging process.
Included in
Life Sciences Commons, Medicinal and Pharmaceutical Chemistry Commons, Natural Products Chemistry and Pharmacognosy Commons, Organic Chemistry Commons