Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713700
Title: Synthesis and evaluation of DNA G-quadruplex ligands and Hsp70 inhibitors
Author: Patel, Alpa
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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Abstract:
Inhibition of the enzyme telomerase is considered to be an anti-cancer strategy with wide scope and the potential to treat all cancers regardless of type. One proposal for targeting this enzyme is via the stabilisation of DNA G› quadruplexes, formed at the very ends of chromosomes and believed to inhibit telomerase from maintaining telomere length. This is thought to prevent the limitless cell division that is a hallmark of cancer. Studies towards the synthesis of DNA G-quadruplex ligands that contain isocytosine or imidazole rings are described herein, including the rationale for their design, synthetic experiments and assessment of a binding interaction through circular dichroism spectroscopy and melting experiments. Optimisation of a promising scaffold was attempted to increase the strength of the stabilising effect on DNA G-quadruplexes, determined by CD melting experiments with telomeric DNA. A total of 10 compounds demonstrated a stabilising interaction with a DNA G-quadruplex-forming oligonucleotide. One series of compounds investigated is structurally similar to a published Hsp70 inhibitor, apoptozole, another prospective anti-cancer molecule that induces apoptosis in tumour cells. The results of a cell viability assay and Western blots that show potential application to this medicinal target are reported and optimisation towards Hsp70 inhibition is described. From this series, 15 compounds demonstrated potency that was equivalent to or greater than apoptozole.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.713700  DOI: Not available
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