Item Details

abstract

The design of novel, small-molecule donors for hydrogen sulfide has received a spotlight of attention in the field of chemical biology research in the last decade. For the purpose of illustrating its potential under an array of physiological conditions, it is important to have a wide range of donors under which it will release. Additionally, a huge question in hydrogen sulfide research remains regarding methods of quantification. During the process of addressing these two overarching research areas, we became quite interested with the larger chalcogen cousin of hydrogen sulfide, hydrogen selenide. With the demonstrated ability for it to act as an antioxidant and its essential role in selenoproteins, we asked if we could engineer previous donors of sulfur to behave in the same mechanism with selenide.In chapter II, we describe the design, synthesis, and evaluation of a novel reaction-based probe for hydrogen sulfide. Many methods that are currently used and cited for detection of hydrogen sulfide hold questions of their specificity towards the gasotransmitter over other nucleophiles. We rationalized that an intermolecular cyclization resulting from electrophilic activation of a selenium-sulfur bond would afford release of a fluorophore reporter. Ultimately, we were able to produce AL1 for initial cell testing and AL2 was able to display cancer cell specificity. In chapter III, we describe a novel and unique ROS-activated scaffold for release of both fluorescent reporters and reactive selenium species. Based on the observed role of the geminal dimethyl group alpha to AL1 in blocking hydrolysis and promoting cyclization, we sought to design a molecule based on previously-reported trimethyl lock scaffolds. With this, we were able to xvi demonstrate our design as specific to hydrogen peroxide and avoid hydrolysis as a side reaction. From this, we were able to synthesize two fluorescent probes for hydrogen peroxide cellular imaging. Additionally, we were able to have this scaffold serve as a donor of both persulfides and hydrogen sulfide. In chapter IV, we further elaborated on the persulfide-releasing scaffold in chapter III and utilized the amide bond in RAH393 to attach a mitochondrial-targeting triphenylphosphonium moiety. In chapter V, we sought to broaden the current scope of hydrogen selenide donors in the literature. Based on the leaving group ability of selenols and hydrogen selenide, we rationalized that if hydrogen selenide was installed in the gamma position to a ketone, ambient keto-enol tautomerization would afford effective release of selenium. Indeed, we were able to demonstrate this via 1H NMR kinetics on four scaffolds, exhibiting tunable rates of release dependent on electron withdrawing capabilities of the respective moieties. Chapter VI describes a new class of enzyme-activated donors inspired by currently published donors of reactive sulfur. Once again rationalizing that selenols and perselenides should exhibit a faster rate of release than thiols and persulfides, we sought to design scaffolds with the intention of releasing in the presence of endogenous esterases.

subject

Hydrogen Selenide

Hydrogen Sulfide

Reactive Selenium Species

Reactive Sulfur Species

Selenium

Lukesh, John C (advisor)

contributor

Hankins , Katherine Ambrose (author)

Smalley, Terrence L (committee member)

Jones, Amanda C (committee member)

King, Stephen B (committee member)

Welker, Mark E (committee member)

date

2023-01-24T09:35:50Z (accessioned)

2022 (issued)

degree

Chemistry (discipline)

2025-01-23 (liftdate)

embargo

2025-01-23 (terms)

identifier

http://hdl.handle.net/10339/101779 (uri)

language

en (iso)

publisher

Wake Forest University

title

CHEMICAL TOOLS FOR DELIVERY AND DETECTION OF REACTIVE SELENIUM AND SULFUR SPECIES: DESIGN, SYNTHESIS, AND EVALUATION

type

Dissertation