Dissertations, Theses, and Capstone Projects

Date of Degree

2-2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Chemistry

Advisor

Ryan P. Murelli

Committee Members

Mark Biscoe

Lesley Davenport

Subject Categories

Chemistry | Organic Chemistry

Keywords

Colchicine AC ring, alpha-methoxytropones, Oxidopyrylium (5+2) cycloaddition, SmI2 ring-opening reaction, Class 3 atropisomerism configurational studies, Chiral resolution of atropisomers

Abstract

Colchicine, a naturally occurring alkaloid, has long been known as a potent therapeutic agent. Despite its efficacy treating gout and other inflammatory disorders, its severe toxicity, limited selectivity, and poor pharmacological profile have restricted its broader clinical application. Reported advantages of colchicine-site ligands as vascular-disrupting agents, including reduced susceptibility to multidrug resistance, have revived interest in the colchicine site on tubulin as a validated therapeutic target for cancer. This dissertation focuses on the development of new colchicine analogs, detailing the synthetic method to functionalized AC-ring derivatives, as well as the evaluation of their configurational stability and biological activity.

In Chapter 1, we provide a literature review that frames atropisomerism within a broader medicinal chemistry context, highlighting classical approaches, synthetic strategies, emerging directions and potential for troponoids as atropisomeric frameworks due to their electronic versatility and capacity for restricted bond rotation.

Chapter 2 describes our synthetic studies on α-methoxytropones. Building upon 3-hydroxy-4-pyrone-based oxidopyrylium [5+2] cycloaddition chemistry, we developed a samarium(II) iodide-mediated reductive ring-opening that efficiently converts oxidopyrylium cycloadducts into methoxytropones. This method provides a modular entry to a family of functionalized tropone scaffolds that had previously been difficult to access. By systematically varying substitution patterns, we demonstrate how methoxytropones can be tuned for stereochemical stability, positioning them as versatile platforms for atropisomerism.

In Chapter 3, we advance these findings to the synthesis of colchicine AC-ring analogs. Guided by computational dihedral-energy profiling and experimental analyses, we identified analogs that exhibit rotational barriers greater than 30 kcal/mol, consistent with class 3 atropisomerism. Herein, we describe the discovery of a stable colchicine-based atropisomer, marking a De Novo synthesis of a new class 3 colchicine atropisomer. Biological evaluation confirmed that one atropisomer retained tubulin inhibitory activity, while its enantiomer was markedly less active. DFT calculations predicted racemization barriers, while chiral HPLC and VCD provided resolution and experimental confirmation of configurational assignments. We also detail the subsequent structural modification strategies toward improving anti-cancer activity. Overall, the study demonstrates the value of integrating predictive computation with experimental validation.

Download

Share

COinS