Elaboration of Diquinanes to Access Trifunctional Angular Triquinanes and Designed DNA Polymerase α Inhibitors

Author

Spencer M. Webber, University of the PacificFollow

Date of Award

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Wade A. Russu

First Committee Member

David Thomas

Second Committee Member

William K. Chan

Third Committee Member

Mamoun Alhamadsheh

Fourth Committee Member

Lisa A. Wrishnik

Abstract

Natural products are of great significance to the pharmaceutical industry in the development of new drugs. Diquinane or bicyclo[3.3.0]octane is a conspicuous structural unit existing in the carbo-frameworks of a wide range of natural products such as alkaloids and terpenoids. These diquinane-containing molecules not only exhibit intriguing architectures, but also showcase a broad spectrum of significant bioactivities, which draw widespread attention from the global synthetic community. A more specific group of compounds containing a diquinane moiety with one extra 5-membered ring are called the angular triquinanes.In this work, we have developed a general synthetic scheme to the angular triquinanes. We envisioned relatively quick access to the angular triquinane ring system, with each ring bearing synthetically useful functionalization, by direct palladium catalyzed [3+2] cycloaddition of a trimethylenemethane (TMM) unit with functionalized bicyclo[3.3.0]octeneones. This was performed with two different realized bicyclo[3.3.0]octenone substrates. The bicyclo[3.3.0]octeneones can be obtained by [3+2] addition of a TMM-based diradical with an olefin. This synthetic approach allows for the access of trisubstituted angular triquinanes with substitution on each of the three rings in the system, conveniently designed for further derivatization into more complex structures. One of the resulting angular triquinanes from our designed synthesis, containing all-cis fused stereochemistry, was further elaborated to display its utility as an easily manipulated angular triquinane containing a ketone equivalent on each of the three rings in the system. Some diquinane intermediates and final triquinane products were subjected to a biological assay to examine potential cytotoxicity against MDA-MB-468 cancer cells. Additionally, we have designed molecules containing both cyclopentane and polyquinane (diquinane and triquinane) ring systems as DNA polymerase α inhibitors based initially on the structure of the known DNA polymerase α inhibitor, aphidicolin. Optimal design was determined and predicted by docking of the designed ligands to the binding pocket in the active site in the crystal structure of DNA polymerase α (4Q5V) through several iterations with the use of Autodock Vina software. Some of the top designed inhibitors with respect to their binding affinity were synthesized in the laboratory and subjected to a human DNA polymerase α assay.

Pages

236

Recommended Citation

Webber, Spencer M.. (2024). Elaboration of Diquinanes to Access Trifunctional Angular Triquinanes and Designed DNA Polymerase α Inhibitors. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/4265