Item Details

title

ADVANCEMENTS IN STIMULUS-RESPONSIVE, H2S-DONATING MOTIFS: DESIGN, SYNTHESIS, AND BIOLOGICAL APPLICATIONS

author

Hu, Qiwei

abstract

Hydrogen sulfide (H2S), as an endogenous signaling molecule, has a great influence on several important (patho)physiological processes related to cardiovascular health and disease, including vasodilation, angiogenesis, inflammation, and cellular redox homeostasis. This dissertation aimed to develop novel H2S donors and H2S-donating prodrugs that mimic its natural enzymatic production to facilitate further investigations into its biological effects and therapeutic potential, especially related to the cardiovascular system. In Chapter I, we compiled a list of synthetic H2S donors that have exhibited protective effects in models of myocardial ischemia-reperfusion (MI/R) injury and cancer chemotherapy-induced cardiotoxicity. In this comprehensive review, we categorized donors by the biological stimulus that triggers their H2S liberation and provided detailed releasing mechanisms. In addition to serving as important investigative tools that further advance our knowledge and understanding of H2S chemical biology, the compounds outlined in chapter I have the potential to serve as vital therapeutic agents for the treatment (or prevention) of various cardiomyopathies. In chapter II, we describe a novel, hydrogen peroxide (H2O2)-responsive, doxorubicin (DOX) hybrid codrug (mutual prodrug) that was rationally designed to concurrently liberate H2S. This mutual prodrug was shown to selectively and simultaneously liberate both H2S and DOX in the presence of biologically relevant concentrations of H2O2. A known cardioprotectant with purported anticancer activity, the released H2S was shown to dimmish the cardiotoxicity of DOX in H9c2 cardiomyoblasts while maintaining its antitumor effects in 4T1 mouse triple negative breast cancer cells in culture. Additionally, rat cardiomyoblasts treated with the H2S-releasing prodrug exhibited higher Nrf2 activation and expression of heme-oxygenase 1 relative to DOX-treated cells. Together, these results suggest significant promise for this prodrug as a cardioprotective chemotherapeutic to replace DOX. In Chapter III, a new and general design strategy was described for increasing the rate, efficiency, and selectivity of H2S liberation from thioamide-based donors through intramolecular nucleophilic assistance, triggered by a specific biological stimulus. Specifically, in this chapter we demonstrated that both disulfide- and diselenide-linked thioamides are responsive to biologically relevant concentrations of glutathione and release H2S via a cyclization reaction that notably enhances the rate and efficiency of sulfide delivery in both buffer and live human cells. Importantly, we predict this general scaffold can be modified to access a wide variety of thioamide-based donors that are selectively responsive to various biological stimuli. To this end, a library of reactive oxygen species (ROS)-activated donors was developed in chapter IV that rely on an analogous cyclization reaction that facilitates H2S release. Unlike previous ROS-responsive donors that typically first liberate carbonyl sulfide (another bioactive gas) enroute to H2S, this donor template directly releases H2S while avoiding the production of electrophilic byproducts. In addition, we identified an ROS-activated, self-reporting donor from this series, which stems from its concurrent synthesis of a benzoxazole-based fluorophore alongside its H2S delivery. This donor class was shown to be highly selective towards ROS, even within a complex cellular environment, and is likely to find many useful applications within a biological setting.

contributor

Lukesh, John JCL (advisor)

Bierbach, Ulrich UB (committee member)

Jones, Paul PBJ (committee member)

Dos Santos, Patricia PCD (committee member)

Poole, Leslie LBP (committee member)

date

2023-07-25T17:48:29Z (accessioned)

2023 (issued)

degree

Chemistry (discipline)

embargo

2024-06-06 (terms)

2024-06-06 (liftdate)

identifier

http://hdl.handle.net/10339/102226 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation