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The development of trackable polynuclear platinum(II) compounds for targeted anticancer applications

O'Carroll, Sinéad orcid logoORCID: 0000-0003-4901-3542 (2022) The development of trackable polynuclear platinum(II) compounds for targeted anticancer applications. PhD thesis, Dublin City University.

Recently, there has been major interest in the design and development of therapeutic polynuclear platinum(II) complexes (PPCs). The potential use for these complexes has been epitomised by BBR3464—a trinuclear platinum(II) complex featuring trans geometry with platinum(II) centres separated by 1,6hexanediamine linkers and terminal trans labile chloride ligands—which was the first and only platinum(II) drug to enter clinical trials not based on the conventional mononuclear cis-chemotype. While this drug class has excellent therapeutic potential, issues regarding off-target toxicity cannot be overlooked. This thesis presents the synthesis, characterisation, cytotoxic analyses, and DNA binding studies of a novel azide-appended polynuclear platinum(II) complex series (N3 -PPCs). These agents feature fully trans-symmetric geometry, vary in nuclearity, and contain a terminal azide to enable biological tracking. Furthermore, although each platinum(II) centre is separated by a 1,6hexanediamine linker similar to BBR3464, this series lack a labile chloride ligand and bind with DNA through a non-covalent mechanism called the phosphate clamp. The stand-out complex in this series, N3 -TriplatinNC, has demonstrated excellent anticancer properties in-vitro in MDA-MB-231 triple negative breast cancer cells and displays impressive in-vivo tumour regression in mice bearing MDA-MB-231 xenografts. Click chemistry labelling studies were conducted to investigate the cellular localisation and accumulation properties of the N3 -PPC series in MDA-MB-231 triple negative breast cancer cell lines. This method of post-exposure ‘click’ modification facilitates accurate detection of the localisation and accumulation properties of the native drug alone. Finally, azide-appended PPCs were functionalised with a thiazole orange (TO) reporter molecule to create the N3 -TO-PPC series. These TO-appended N3 -PPCs were studied for their DNA binding properties and results were compared to the aforementioned N3 -PPCs and earlier reported PPCs. Future work on the TO appended PPCs entails cellular tracking within MDA-MB-231 cell lines and compared to non-TO modified congeners.
Item Type:Thesis (PhD)
Date of Award:February 2022
Supervisor(s):Kellett, Andrew
Subjects:Medical Sciences > Cancer
Physical Sciences > Chemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
Funders:Science Foundation Ireland
ID Code:26596
Deposited On:17 Feb 2022 13:24 by Andrew Kellett . Last Modified 17 Feb 2022 13:24

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Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0


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