An investigation into the cytotoxicity of cis,cis-triaminocyclohexane derivatives

Luisa Ciano

    Research output: ThesisDoctoral Thesis

    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.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of York
    Supervisors/Advisors
    • Walton, Paul H, Supervisor, External person
    • Lynam, Jason M., Supervisor, External person
    Award date16 Jul 2014
    Publication statusPublished - Sept 2013

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