Date of Award

12-16-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Binghe Wang

Second Advisor

Maged Henary

Third Advisor

Suazette Mooring

Abstract

Carbon monoxide (CO) is formed endogenously and plays various essential physiological and therapeutic functions. In the field of organic synthesis, CO is an important C1 synthon for building complex molecules. However, delivery of CO in the gaseous form presents challenges such as toxicity, storage, and dosage control. Therefore, there is considerable research interest in the development of approaches to cage CO in a form that is easier to store, handle, and deliver. Various chemical strategies to cage CO for therapeutic and synthetic applications are described herein.

Because of its pleiotropic effects, CO is a good candidate for combination therapy. A prodrug strategy that relies on a three-reaction cascade leading to the release of more than one drug component with the generation of a fluorescent side product for easy monitoring was developed. As a proof of concept, co-delivery of CO with the antibiotic metronidazole was demonstrated. The utility of this strategy was demonstrated in an in vitro model wherein administration of the cascade prodrug led to 26-fold sensitization of H. pylori against metronidazole.

With the goal of achieving pharmaceutically viable “CO in a pill”, we developed a new class of CO prodrugs that is based on benign carriers that have well-established safety profiles. With CO caged in a dicarbonyl moiety, we attached FDA-approved non-calorific sweeteners as the leaving groups. This ensemble cages CO in a stable prodrug that relies on hydrolysis to deliver CO. This CO prodrug recapitulated anti-inflammatory effects of CO against LPS-induced TNF-𝛼 production. Furthermore, oral administration of the prodrug led to an elevation of COHb in mice indicating its pharmaceutical viability as a CO prodrug.

We developed a visible light-activated CO donor/surrogate for carbonylation reaction. This solid CO reagent is easily synthesized from readily available starting materials, stable under ambient light, requires readily available low-power blue LED for activation, and releases two equivalents of CO. Using this donor, a simple, one-pot, glovebox-free protocol was successfully implemented in conventional palladium-catalyzed carbonylative transformations. Distinctively, this CO donor has been shown to be especially compatible with light-assisted carbonylation of conventionally inaccessible substrates such as alkyl halides and bulky nucleophiles.

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