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PHOTO-REVERSE CLICK CHEMISTRY AND SYNTHESIS OF SPILANTHOL AND ITS DERIVATIVES

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title
PHOTO-REVERSE CLICK CHEMISTRY AND SYNTHESIS OF SPILANTHOL AND ITS DERIVATIVES
author
Zhu, Yunhuang
abstract
This dissertation is generally divided into two parts. The first part discusses experiments about the natural compound, spilanthol (SPL), as an anti-chlamydia drug. The second part is focused on the development of a new concept of reverse-click reaction. The compounds we discovered can potentially couple with azides with copper(I) catalyzed 1,3- Huisgen (click) reaction, and be cleaved into the amine, which has the same main structure as the starting azide.Chapter 1 gives an introduction of photochemical pathways and principles. After that, a brief discussion of electronic transition between molecule orbitals in excited states is given. Further, the spin states related to a molecule in its excited state and the mechanism behind the phenomenon of intersystem crossing are presented. Moreover, the chemistry about the singlet oxygen is summarized. It is a reactive molecular generated by oxygen with the help of light and photosensitizer. The reactions of singlet oxygen are mentioned in this part. In the end, the background of photocyclization reaction is established. And a introduction of click chemistry will also be given. Chapter 2 described the studies on Spilanthol. The part was done collaboratively by my coworkers from Dr. Furdui’s group and Dr. Tsang’s group in Wake Forest University School of Medicine and me. Spilanthol (SPL), and the peroxidation product of Spilanthol (SPL endoperoxide, SPLE), were chemically synthesized and showed different potent anti-chlamydial activity in cell milieu. Comparison of SPL and SPLE reactivity with mammalian peroxiredoxins, demonstrated preferred reactivity of SPLE with Prx3, and virtual lack of SPL reaction with any of the reduced Prx isoforms investigated. Cumulatively, these findings support the function of SPL as a pro-drug, which is converted to SPLE in the cellular milieu leading to inhibition of Prx3, increased mitochondrial oxidation and disruption of F-actin network, and inhibition of Chlamydia trachomatis (Ct) infection. Chapter 3 exhibits the synthesis of the SPL derivatives. In order to analyze the structure activity relation (SAR) of the SPL toward inhibition of Ct, many compounds have been designed and synthesized. Those compounds share similar structure with SPL, but each has a single variation on functional groups or length of the link. Biological tests on those SPL derivatives are underway, and some results will be demonstrated in this chapter. Three compounds that are SPL-conjugates have been made. They all kept facets of the original SPL structure, but coupled with a particular functional tag. We will use them to determine what kind of protein the SPL interact with in the cells and whether it works in mitochondria or not. Chapter 4 reported how the reverse-click chemistry experiments have been carried out. Different substrates have been designed with multiple mechanisms, including direct radical generation, photo-driven mechanism generation and photocyclization. They all have been synthesized and analyzed under irradiation reaction in order to examine their capability of reverse-click reaction. Chapter 5 was focused on the detailed discovery on the specific reverse click chemistry I designed. The reaction condition was optimized. Reverse click reaction on different substrates has been evaluated. Some kinetic studies on the reverse click reaction were analyzed with HPLC and UV detection.
subject
click chemistry
Organic synthesis
Photochemistry
Spilanthol
contributor
Jones, Paul B (advisor)
Bierbach, Ulrich (committee member)
Jones, Amanda C (committee member)
Furdui, Cristina M (committee member)
King, Stephen B (committee member)
date
2023-06-07T08:35:39Z (accessioned)
2024-06-06T08:30:08Z (available)
2023 (issued)
degree
Chemistry (discipline)
embargo
2024-06-06 (terms)
identifier
http://hdl.handle.net/10339/102107 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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