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ADVANCEMENTS IN CHALCOGEN CHEMISTRY: THE SYNTHESIS AND BIOLOGICAL EVALUATION OF SELF-REPORTING, H2S DONORS AND A NEW SYNTHETIC METHOD FOR ACCESSING 3-SELENYLQUINOLINES

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title
ADVANCEMENTS IN CHALCOGEN CHEMISTRY: THE SYNTHESIS AND BIOLOGICAL EVALUATION OF SELF-REPORTING, H2S DONORS AND A NEW SYNTHETIC METHOD FOR ACCESSING 3-SELENYLQUINOLINES
author
Zhu, Changlei
abstract
Hydrogen sulfide (H2S) is an endogenous signaling molecule that has been shown to provide impressive antioxidative and cytoprotective effects. To further gauge its physiological and pathophysiological properties, small molecule donors with precise control over their H2S delivery within a biological setting are needed. However, one challenge in H2S donor development is the spatiotemporal feedback from exogeneous H2S in living cells. Current methods for the detection of H2S, including the Methylene blue assay, H2S-selective electrodes, and H2S-selective probes/sensors, are either not appropriate for non-homogeneous biological samples or not suitable for the real-time monitoring of the generation of H2S. To meet the requirements for the detection of H2S in vitro and in vivo, great efforts have been made by introducing fluorescent reporter to the donors which make it possible for tracking the real-time release of H2S from the donors. A summary of the current self-reporting H2S donors is demonstrated in Chapter I. Based on the stimuli, these donors could be categorized as bio-thiols, reactive oxygen species (ROS), enzymes, pH-hydrolysis, light-photo, and bio-orthogonal activated. To better understand the generation of H2S, the detailed mechanisms are presented as well. Some of these donors are found to be organelle targeted, which provides an insight into the biological activities of H2S towards different organelles. Also, broadening the design of H2S donors and other chemical tools to deliver gasotransmitters. In Chapter II, we describe a novel, self-reporting H2S donor that is selectively activated by reactive oxygen species (ROS). Within our design, we append an ROS-responsive aryl boronate ester to 7-hydroxy-4-methylcoumarin via an S-alkyl thiocarbonate linkage—a key feature which provides the efficient release of both H2S (via COS hydrolysis) and a fluorescent reporter in response to elevated levels of ROS. Thus, this design was found to provide a useful bifunctional tool given its rare ability to simultaneously image and neutralize hydrogen peroxide within live cells. This chapter was published on Tetrahedron Letters (Tetrahedron Letters. 2021, 69, 152944). In Chapter III, through intramolecular nucleophilic assistance, we recently described a new and general design strategy for increasing the rate and efficiency of H2S release from thioamide-based donors. In the present study, we utilize this new chemistry to access a novel reactive oxygen species (ROS)-activated, self-reporting donor, which stems from its concurrent synthesis of a benzoxazole-based fluorophore alongside its H2S delivery. Inspired by our previous work and related references, we developed a library of H2S donors which selectively respond to esterase. Within this design, a series of ester groups rather than boronate ester were appended to the H2S scaffold. These thioamide-based donors would deliver H2S along with the formation of a benzoxazole-based fluorophore through an intramolecular cyclization. To the best of our knowledge, this would be the first example of enzyme activated H2S donors with fluorescent reporter to indicate the real-time generation of H2S. Chapter V is different from Chapter II, Chapter III, and Chapter IV, in this chapter, an efficient and novel approach to accessing 3-selenylquinolines from diaryl diselenides and acyclic, selenium-free substrates is described. Preliminary mechanistic studies indicate that the combination of CuCl2 and air affords an appropriate environment for producing arylselenyl radicals that initiate the cascade cyclization of N-(2-alkynyl)anilines, forming key Se−C and C−C bonds in a single step. Using this chemistry, a wide variety of 3-selenylquinolines were produced in moderate to excellent yield under mild conditions, highlighting the versatility and usefulness of this new method. This chapter was published in Journal of the Organic Chemistry (J. Org. Chem. 2022, 87, 8390−8395).
subject
3-selenylquinolines
Cellular protection
Fluorescent probes
Hydrogen sulfide
self-reporting
Theranostics
contributor
Lukesh, John C (advisor)
Zhang, Ke (committee member)
Jones, Paul B (committee member)
King, Bruce S (committee member)
Stich, Troy (committee member)
date
2024-02-13T09:36:07Z (accessioned)
2023 (issued)
degree
Chemistry (discipline)
embargo
2024-08-12 (terms)
2024-08-12 (liftdate)
identifier
http://hdl.handle.net/10339/102910 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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