Date of Award

12-16-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Binghe Wang

Second Advisor

Kathryn Grant

Third Advisor

Suazette Mooring

Abstract

As endogenously produced small molecules, hydrogen sulfide (H2S) and carbon monoxide (CO) have been demonstrated in extensive studies to mediate cellular signaling. More importantly, the therapeutic effects of these small molecules have been validated in vitro and in vivo. As such, development of H2S- and CO-based therapeutic agents have attracted great interests in recent years.

H2S is known to undergo redox transformations in biological systems to produce various sulfur species such as glutathione persulfide (GSSH) and cysteine persulfide (CysSSH). Several studies have indicated the enhanced ability for persulfides to modify protein through S-persulfidation and to quench reactive oxygen species (ROS) as compared with H2S. These findings raised the potential importance of persulfide species in as a signaling molecule. Generally speaking, persulfides are not chemically stable for storage under near physiological conditions. This lack of stability presents difficulties in formulating and delivering such molecules for research and therapeutic purposes. In Chapter 1, we describe the development of stable prodrug forms of persulfide for various applications. In doing so, we explored the stability issues of persulfides under near physiological conditions. The biological activities of these prodrugs were also examined and compared with that of H2S.

In the field of developing CO as therapeutic agent, ruthenium-based CO releasing molecules (CO-RMs), CORM-2 and CORM-3, have been widely used as CO surrogates. However, several previous studies have revealed the ability for such CO-RMs to chemically modify proteins through CO-independent mechanisms, raising concerns of the suitableness for CORM-2, 3 as CO surrogates in biological studies. In Chapter 2, we reported our findings on CO-independent reactivities of CORM-2, 3 toward representative reagents commonly used in various bioassays. These results suggest the need to carefully de-convolute and interpret the biological data from relevant experiments using ruthenium-based CO-RMs as surrogates of CO for probing its biological effects.

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