Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.595164
Title: An investigation into the cytotoxicity of cis,cis-triaminocyclohexane derivatives
Author: Ciano, Luisa
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2013
Availability of Full Text:
Access from EThOS:
Access from Institution:
Abstract:
N,N’,N’’-Tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane, tachpyr, has been studied for several years for its potential application in cancer therapy. Several studies have been carried out to understand the mechanism of action of this molecule and Planalp and co-workers have reported evidence to support the hypothesis that iron chelation, followed by iron deprivation in cells, are a likely reason for cytotoxicity. We have investigated the properties of tachpyr with the aim of improving cytotoxicity and gaining a deeper understanding of its mechanism of action. A series of tach-based ligands were synthesised with the purpose of modifying the general structure of tachpyr and evaluating the pharmacophores necessary for activity. The biological evaluation of the mechanism of action involved various techniques, such as dichroism and X-ray crystallography, and the anti-proliferative activity of all tri-amine compounds was evaluated with in vitro tests against tumour cells. A series of experiments to monitor the effect of increasingly higher concentrations of Fe on the toxicity of tachpyr against tumour cell lines were performed. These results disagree with those previously reported in the literature and show that the cytotoxicity of tachpyr is independent of the concentration of Fe (up to 400 µM), which is inconsistent with the proposed mechanism of action. A different cellular target was investigated. Binding experiments with DNA showed an interaction with tachpyr and co-crystallisation with a short DNA oligonucleotide produced crystals suitable for X-ray diffraction. Analysis of structure activity relationships gave insights on the essential features of these molecules to retain anti-proliferative activity. The data obtained and presented in this thesis suggest a completely new potential mechanism of action for this class of compounds.
Supervisor: Walton, Paul H. ; Lynam, Jason M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.595164  DOI: Not available
Share: