Dissertations, Theses, and Capstone Projects

Date of Degree

2-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Ryan Murelli

Committee Members

Mark Biscoe

Kevin Ryan

Subject Categories

Chemistry | Medicinal-Pharmaceutical Chemistry | Organic Chemistry

Abstract

Troponoids are a class of non-benzenoid aromatic species featuring a cycloheptatrienone ring and varying degrees of oxygenation. These scaffolds have proven ubiquitous amongst natural products, and have displayed promise as therapeutic agents against a variety of diseases. Herein, we will describe our efforts towards furthering troponoids as potential pharmaceuticals. In Chapter 1, we outline a kojic acid-derived oxidopyrylium cycloaddition/ring-opening method developed in our lab to generate ahydroxytropolones (aHTs). This route was successfully adapted to synthesize a small library of lipophilic aHTs that were proven to be effective against herpes simplex virus-1 (HSV-1) replication, while providing further insight into the mechanism of troponoid-based HSV-1 inhibition. In Chapter 2, we adapt the oxidopyrylium cycloaddition method to allow for the incorporation of acid-sensitive groups onto the aHT core. We outline our efforts at developing a mild, late-stage direct amidation of aHTs that has enabled access to a range of previously inaccessible functionalities. This amidation methodology was also successfully utilized on tropolone and tropone-containing substrates, proving to be an effective method for amidotroponoid synthesis. v In Chapter 3, we provide a literature review of tropolone syntheses arising from diazo-derived ring expansions. We then describe our discovery and optimization of an ambient air-promoted autoxidation of Buchner ring expansion-derived cycloheptatrienes into aromatic tropolones. The scope and generality of this reaction was assessed, and empirically obtained data supported a robust hypothesis for the putative mechanism of autoxidation. In Chapter 4, a class of amidotroponoids containing a light-reactive diazirine moiety and alkyne reporter tag were assessed for their potential as activity-based probes. The troponoid probes covalently labeled proteins in a live cell line of HEK-293T cells in a UVand concentration-dependent manner, enabling the preliminary identification of novel troponoid protein targets. Additionally, the experiments revealed the ability of troponoids to covalently photolabel proteins in the absence a known photo-labile moiety. The mechanism of this photolabeling, in addition to the characterization of an analogous troponoid-amino acid adduct, is investigated.

Download

Share

COinS