Date of Award
Ph.D. in Pharmaceutical Sciences
John M. Rimoldi
David A. Colby
Robert J. Doerksen
The terrestrial organisms Streptomyces venezuelae and Rhaponticum repens produce toxic secondary metabolites that likely function as chemical deterrents. The polyketide SV-6 from S. venezuelae and the sesquiterpene lactone repin from R. repens both produce dose-dependent and selective degeneration of dopaminergic neurons. These molecules represent two possible tools that can be used to explore chemotoxic induction of Parkinson’s disease. In the case of SV-6, a newly isolated metabolite, total synthesis was undertaken to confirm its structure and biological activity. The natural product was produced from methacrolein and Roche ester starting materials that were elaborated to their respective fragments, a vinyl iodide and a Weinreb amide. These fragments were coupled to form SV-6 and the synthesis allows for many additional opportunities to easily generate stereoisomers and analogs for further study. In the case of repin, previously isolated material was used as a starting material to create a biotin-labeled probe. There were considerable challenges due to the electrophilic nature of the compound, but a Nicolas reaction folloby copper catalyzed cycloaddition produced an impure biotin-repin probe. Repin was also subjected to screening in multiple biological assays which identified proteins potentially responsible for its neurodegenerative activity.
Cunningham, Michael John, "Synthetic Investigation of Natural Products Causing Dopaminergic Neurodegeneration" (2018). Electronic Theses and Dissertations. 1457.
Emphasis: Medicinal Chemistry