Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620784
Title: Synthesis and evaluation of small molecules for controlling stem cell development
Author: Zhou, Garr Layy
ISNI:       0000 0004 5359 1078
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2014
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Abstract:
Retinoids are a class of signalling molecules that includes vitamin A along with its natural and synthetic analogues. Retinoids regulate important biological pathways from embryogenesis through to adult homeostasis, and influence the proliferation and differentiation of a variety of cell types. The effects of retinoids are primarily mediated through binding to and activation of the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Three subtypes of RARs exist: RARα, RARβ and RARγ. Isoforms for each of these receptor subtypes are known, with the RARβ2 isoform in particular known to stimulate neurite outgrowth. The design of isoform-selective ligands is thus an important area to allow investigation into the mechanism of activity of the individual RAR isoforms. Syntheses of the proposed RARβ2 agonists containing phenyl- and tetramethyltetrahydronaphthyl-substituted side chains are described herein. These thiazole-containing small molecules were assessed for activity in inducing the differentiation of human pluripotent TERA2.cl.SP12 embryonal carcinoma (EC) cells, with the more bulky tetramethyltetrahydronaphthyl analogue able to induce differentiation of this cell line to a level comparable to that of the natural retinoid, ATRA. Furthermore, at 0.1 µM, this analogue promoted enhanced neural commitment and neurite outgrowth over ATRA, with levels similar to that observed with the synthetic retinoid EC23. The second part of this thesis concerns the synthesis of a fluorescent retinoid, GZ108, and preliminary assessments of its fluorescence and biological activities. In an effort to optimise the synthetic route and to improve compound stability, the preparation of N-acetyl, amide, and oxazoline analogues are also discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.620784  DOI: Not available
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