Date of Award

5-6-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Dr. Binghe Wang

Second Advisor

Dr. Gangli Wang

Third Advisor

Dr. Suri S. Iyer

Abstract

Carbon monoxide (CO) is an endogenously produced gasotransmitter in mammals and may have signaling roles in bacteria as well. It has many recognized therapeutic effects. A significant challenge in this field is the development of pharmaceutically acceptable forms of CO delivery with controllable and tunable release rates. Our lab has designed a series of organic CO prodrugs as prototypes of “carbon monoxide in a pill.” In the first project, a series of such CO prodrugs was synthesized to examine the structure-release rate in aqueous solution at neutral pH.

CO prodrugs with triggered release mechanisms are highly desirable for targeted delivery. In the second project, we focused on the development of reactive oxygen species ROS-sensitive CO prodrugs, which selectively deliver CO to cells with elevated ROS levels and sensitize cancer cells to chemotherapy. CO prodrugs as such could serve as powerful tools for targeted delivery to disease sites with elevated ROS levels and for exploring the therapeutic applications of CO.

In the third project, we focused on metal-free CO prodrugs with dual-responsive endogenous triggers, which have the advantage of controlled activation at the desired site of action. These CO prodrugs afford highly selective release profiles as compared to others with no or a single trigger. In addition, one representative CO prodrug showed significant anti-inflammatory effects both in vitro and in a LPS-simulated systemic inflammation models, suggesting its possible application in treating systemic inflammatory conditions. The prodrug also conferred very pronounced protective effects against LPS-induced acute liver injury. These results firmly established such CO prodrugs as either research tools or candidate compounds for the treatment of systemic inflammation or other inflammation-related organ injuries.

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