Date of Award
1-1-2024
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Robert J. Doerksen
Second Advisor
Sudeshna Roy
Third Advisor
Jonah W. Jurss
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Historically, nature has served as the largest source of inspiration for drug discovery. From the first isolations of antimicrobial compounds to the development of novel therapeutic agents, natural product-inspired drug discovery has been instrumental in identifying novel therapeutics to aid in mankind’s interminable fight against diseases. This dissertation introduces natural product-inspired drug discovery and development. Telling the story of mankind’s discovery and continual development of medicine and medicinal chemistry, this introduction is separated into six key historical periods. While these periods are markedly different, what remains consistent throughout the history of natural-product inspired drug discovery and development is humanity’s tireless efforts to fight, and even eradicate, endemic disease.
For instance, one of the most famous examples—emblematic of this inexhaustible spirit—of drug discovery from natural products is the discovery of artemisinin for the treatment of malaria, which was awarded a Nobel Prize in medicine in 2015. Our lab has systematically classified antimalarial drugs, including those of natural products and those that were inspired by natural products, in a book chapter in the textbook “Medicinal Chemistry of Chemotherapeutic Agents” that was just published by Elsevier/Academic Press.
One major approach in natural product-inspired drug discovery is to develop novel synthetic methods or novel synthetic routes to quickly synthesize the core structures of natural products, such as substituted heterocycles, to generate novel compounds for the screening of biological activities. For example, imide is an important functional group in many natural products and pharmaceuticals. As part of our lab’s ongoing efforts to develop new environmentally friendly methods for the synthesis of highly substituted and functionalized heterocycles, a new hydrolytic procedure converting N-acyl amidines to imides in the presence of sodium azide under very mild conditions was discovered. This method proceeds in the presence of acetic acid and at room temperature to give moderate-to-high yields of imides in two hours, and works in the conversion of amines to ketones, and the conversion of imines to aldehydes.
Our lab has also discovered a method that selectively synthesizes 1,6-disubstituted carbazoles over 3,6-disubstituted carbazoles. Both 1,6-disubstituted carbazoles and 3,6-disubstituted carbazoles are important scaffolds in many antimicrobial and antitumor compounds and are valuable starting points for drug discovery and development. In our synthetic method, ethyl 6-azido-3' (hydroxymethyl)-[1,1'-biphenyl]-3-carboxylate (IV.1) was initially converted into the corresponding 1,6-disubstituted carbazole product in the presence of o-xylene in a 31% yield. A subsequent attempt to increase the yield of the product using catalyst did not afford a higher yield. During attempts to synthesize IV.1, 3,6-disubstituted carbazoles were not observed to be formed. However, during the synthesis of further 1,6-disubstituted carbazole derivatives, it was discovered that for some substrates the method allowed for the 1,6- and 3,6-disubstitued carbazole products to form. The proportion of products in a reaction mixture, when present, was not consistent across examples, and, so far, there are as many examples demonstrating the formation of a potential product mixture as there are demonstrating the selective synthesis of 1,6-disubstituted products. The reaction conditions will be optimized, and the scope of the substrates will be explored for this newly discovered synthetic method. The future directions presented represent future research of each chapter that would be meritorious.
Recommended Citation
Saucier, Matthew Albert, "Progress in Synthetic Methodology Development for Natural Product Inspired Drug Discovery" (2024). Electronic Theses and Dissertations. 2976.
https://egrove.olemiss.edu/etd/2976