Synthesis of kainic acid derivatives and their application as kainate receptors probes
department or school: Arts and Sciences, Irving K. Barber School of (Okanagan)
department or school: Chemistry, Department of (Okanagan)
data provider: DSpace
degree campus: UBCO
creator: Tian, Zhenlin
issued: 2019-07-04T18:28:31Z
issued: 2019
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Kainate receptors play important roles in the central nervous system. However, investigating their role in physiology is hampered by the current lack of tools to study them in dynamic cellular contexts. This thesis describes the synthesis of C4-kainoids and their derivatives, which are designed to serve as chemical probes to study kainate receptors in neurobiology. Chapter 1 provides a brief introduction of kainate receptors’ roles in central nervous systems and an overview of existing probes for glutamate receptors. Chapter 2 presented a comprehensive structure/activity analysis for efficient KARs ligands. This chapter reviews all reported kainic acid analogs that have been biologically tested and identifies systematic trends in biological activity of these analogs. These trends combined with protein crystallographic studies led us to identify structural guidelines that must be respected to design the next generation of efficient ligands for kainate receptors. These guidelines informed our synthetic design of the kainoid chemical probes presented in subsequent chapters. Chapter 3 focuses on the development of a synthetic strategy of kainic acid analogs that: (1) is short, (2) is high-yielding and scalable, and (3) allows easy variation of substituents at the C4 position of kainic acid. It resulted in a general stereoselective synthesis of 4-substituted kainoids: kainic acid and its natural isomers were synthesized in 8 to 11 steps from the commercially available 4hydroxyproline. The sequence also enables a late-stage modification of C4 substituents with sp 2 nucleophiles. Stereoselective steps include a cerium-promoted nucleophilic addition and a palladium-catalyzed reduction. A 10-step route to a carboxylic acid derivative was also established to enable ready functionalization of the C4 position. This work represents the first unified synthetic route to C4 derivatives of kainic acid. Chapter 4 describes the synthesis of kainoid derivatives that bear a fluorescent …
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/70906
note: SYNTHESIS OF KAINIC ACID DERIVATIVES AND THEIR APPLICATION AS KAINATE RECEPTORS PROBES by Zhenlin Tian B.Sc., Hubei University of Technology, 2010 M.Sc., East China University of Science and Technology, 2013 A thesis submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in THE COLLEGE OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) July 2019 © Zhenlin Tian, 2019 ii The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a thesis/dissertation entitled: Synthesis of kainic acid derivatives and their application as kainate receptors probes submitted by Zhenlin Tian in partial fulfillment of the requirements of the degree of Doctor of Philosophy in Chemistry . Dr. Fred Menard, Department of Chemistry, UBC Okanagan Supervisor Dr. Paul Shipley, Department of Chemistry, UBC Okanagan Supervisory Committee Member Dr. Isaac T.S. Li, Department of Chemistry, UBC Okanagan Supervisory Committee Member Dr. Gregory Dake, Department of Chemistry, UBC Vancouver University Examiner Dr. Jeffrey Keillor, Department of Chemistry and Biomolecular Sciences, University of Ottawa External Examiner ii Abstract Kainate receptors play important roles in the central nervous system. However, investigating their role in physiology is hampered by the current lack of tools to study them in dynamic cellular contexts. This thesis describes the synthesis of C4-kainoids and their derivatives, which are designed to serve as chemical probes to study kainate receptors in neurobiology. Chapter 1 provides a brief introduction of kainate receptors’ roles in central nervous systems and an overview of existing probes for glutamate receptors. Chapter 2 presented a comprehensive structure/activity analysis for efficient KARs ligands. This chapter reviews all reported kainic acid analogs that have been biologically tested and identifies systematic trends in biological activity of the…
has type: Thesis/Dissertation
date issued: 2019-09
is shown at: 10.14288/1.0379756
language: eng
degree discipline: Chemistry
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/70906