Date of Award
PhD (Doctor of Philosophy)
Dr Darren Griffith
Apjohn Chemistry Scholarship, RCSI
Metal Anticancer Drugs, Platinum, Click Chemistry
Click Chemistry represents an exciting and important branch of synthetic chemistry with vast potential. Due to its versatility it is frequently used to modify and functionalise drugs, sensors and macromolecules for example, facilitating important advancements in many scientific fields. Furthermore, given its ability to generate unique compounds with relative simplicity, it is now at the forefront of modern chemical synthesis. This thesis explores how click chemistry conjugation strategies can be developed to functionalise Pt based drugs.
Cancer is one of the leading health issues worldwide, with 1 in 6 deaths being cancer related. Pt based drugs are used in 50% of all chemotherapy regimens. Despite the many successes of Pt drugs, the negative side effects associated with treatment often limit their effectiveness. In addition, many cancers become resistant to Pt based therapy over time. This thesis explores how click chemistry can play a role in enhancing the activity of Pt-based drugs and tracking Pt-based drugs through functionalisation.
Chapter 1 primarily provides an introduction to cancer, the medicinal chemistry of Pt-based drugs and click chemistry. A summary of research undertaken to date in relation to conjugation of Pt centres to secondary molecules is also provided.
Chapter 2 outlines the methods used to synthesise a number of novel organic compounds and ligands, as well as inorganic complexes. Peptide synthetic methods are also described, in addition to biological, in vitro and fluorescent imaging techniques and methods used.
Chapter 3 describes the development of a novel biocompatible Pt-fluorophore click complex and how the conjugation of a NIR fluorescent probe to a Pt drug may further our understanding of Pt cellular uptake and distribution. A Cu-free technique (SPAAC) was employed; the first of its kind, where the azide handle resides on the stable ammine carrier ligand. The in vitro cytotoxicity, DNA binding properties and widefield microscopy cellular imaging of the novel Pt-fluorophore complex were investigated. viii The selective targeting of cancer cells over healthy cells is of prime interest in chemotherapeutic research, as the non-selective nature of Pt drugs is one of the biggest drawbacks associated with their use clinically. In addition, resistance to current Pt chemotherapy regimens is of major concern.
Chapter 4 explores how peptides may be used to selectively target cancer and improve the potency of Pt drugs. The development of a novel Pt(IV)-peptide conjugate and its in vitro cytotoxicity is described. Chapters 5 and 6 focus on synthesis of novel ligand scaffolds synthesised through click chemistry strategies with an emphasis on generating dual functional metal based drug complexes.
In chapter 5, the synthesis of a novel 1,4-disubstituted 1,2,3-triazole based multidentate ligand is described. Reaction of this ligand with Pt(II) and Au(III) precursors afforded novel complexes, the structures of three of which were characterised by X-ray crystallography, featuring interesting coordination modes. 1,4-disubstituted 1,2,3-triazole based multidentate ligands are demonstrated to be ideal platforms for the generation of multinuclear and mixed metal complexes.
Finally, chapter 6 features three independent subsections, which build on outputs from chapters 3 and 5 and describes the development of (i) click capable cage ligands, (ii) Pt-steroid complexes for enhanced cancer targeting and (iii) iEDDA capable Pt-tetrazine complexes.
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Kitteringham E. Functionalisation of Platinum Based Drugs Through Click Chemistry Strategies [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2018.
Available for download on Friday, November 15, 2019