Transition metal complexes have been successfully employed for medicinal use by exploiting the advantageous properties of the metal centre. Diversifying the current commercially available drugs is required due to their drawbacks, both the external and internal side-effects. Photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) agents offer a less invasive, more efficient, and potentially safer alternative. The use of ruthenium and osmium metal centres have recently been investigated as these display advantageous properties in their use as PDT/PACT agents, for absorption and emission of low-energy light with a large Stokes shift, and as they are also thermally inert and non-toxic in the dark. Most prominently TLD1433 reaching human clinical trials and the osmium analogue Os-4T which displayed unprecedented hypoxic phototoxicity. Osmium and ruthenium metal complexes have also been utilised as cellular imaging agents. The high extinction coefficients, good emission quantum yields, aqueous solubility, high cell permeability, low cytotoxicity, high chemical stability and high photostability give these complexes high potential for use in biological applications. Modification of the ligand set around the metal can alter the localisation point in a cell and ultimately the application of each complex. Further development of such systems, which can be used for medicinal purposes, is consequently essential. Incorporation of the 1,4-disubstituted 1,2,3-triazole motif, prepared using a copper(I)-catalysed 1,3-dipolar cycloaddition of azides and alkynes (CuAAC) reaction, would offer versatility of the ligand surrounding the metal centre. Relatively simple and cheap procedures using mild conditions would give easily purifiable ligands, with potential to attach biologically relevant motifs. Herein, this work will look at merging the valuable properties of the osmium and ruthenium metal centres with the 1,4-disubstituted 1,2,3-triazole ligands, and other biologically relevant ligands, to prepare, characterise and examine their properties. This thesis will present the results as potential PDT/PACT/biological imaging agents. Chapter 3 describes the preparation of heteroleptic Ru(II) 1,4,5,8-tetraazaphenanthrene (TAP)/1,1'-dibenzyl-4,4'-bi-1,2,3-triazolyl (btz) complexes as potential PACT agents. The photochemical activity is hypothesised to change as substitution of one photochemically active ligand with another occurs, with potential to have competitive photochemistry between the two ligands. The photochemical mechanisms of the respective complexes were investigated and fully deduced. It was indeed found that the bis-TAP complex, [Ru(TAP)2(btz)][PF6]2, displayed competitive photochemistry, with the mono-TAP complex, [Ru(TAP)(btz)2][PF6]2, exhibiting only btz release. Photophysical and computational studies rationalise the switch in photochemical activity between the two complexes. Preliminary studies on healthy and cancerous cell lines were also conducted. Chapter 4 describes the preparation of heteroleptic Ru(II) complexes bearing bi-1,2,3-triazole ligands with variation of diimine (N^N) ancillary ligands as potential PACT agents. The photochemistry of the two groups of complexes, [Ru(N^N)(btz)2][X]2 and [Ru(N^N)2(btz)][X]2 (X = PF6- or Cl-), is investigated, with particular interest in their respective photochemical quantum yields. The photophysical effect of exchanging ligands is investigated and the subsequent consequences that may have on the photochemical quantum yields. It was ascertained that the smaller the HOMO-LUMO gap, the more efficient the population of the 3MC states and therefore larger photochemical quantum yields. Upon chloride metathesis, the preliminary (photo)biological studies were also examined on healthy and cancerous cell lines. Chapter 5 describes the larger-scale preparation of the photoproducts prepared in other Chapters. The photochemistry of the Ru(II) trans-bis-solvento bi-1,2,3-triazole complexes is investigated for potential application as PACT/DNA intercalators. The novel photochemistry of the complexes is investigated to discern the photochemical lability of the acetonitrile ligands. The investigation into the photochemical effect the replacement of the N^N ligands has on the photochemical quantum yields is also conducted. It was determined that the smaller the HOMO-LUMO gap, the photochemical quantum yields were larger due to more efficient population of 3MC states. The photochemical quantum yields also allowed for the confirmation that the solvento ligand loss is far more favourable than the formal loss of the btz ligand in the intermediate trans-[Ru(N^N)(2-btz)(1-btz)(d3-MeCN)]2+ complexes reported in Chapter 4. Preliminary studies on healthy and cancerous cell lines were also conducted. Chapter 6 describes the preparation of Ru(II) and Os(II) dppz (dipyrido[3,2-f:2′,3′-h]-quinoxaline) and tppz-containing (tetrapyrido[3,2-a:2′,3′-c:3′′,2′′-h:2′′,3′′-j]phenazine) complexes as potential DNA binders and dual modal PDT/PACT agents, including two novel dinuclear complexes. Complexes bearing dppz and tppz ligands are known to DNA intercalate with the dppz ligand being famous for its “light-switch” effect capabilities. The photochemical properties of the Ru(II) complexes will be investigated to understand the effect these extended biologically relevant ligands have. The change in photophysical properties is investigated when exchanging the metal centre to Os(II). The Os(II) based complexes exhibited favourable spin-forbidden direct excitations to the 3MLCT states extending the absorption further into the red region. The dinuclear ruthenium complexes were also observed to be photochemically active. Preliminary studies on healthy and cancerous cell lines were also conducted. [Os(TAP)2(dppz)]2+ underwent more in-depth studies due to collaborations with the University College Dublin and the Slovenian NMR centre. Chapter 7 describes the preparation of Os(II) bi-, tetra- and penta-1,2,3-triazole complexes with long-lived excited states for biological imaging or PDT applications. The long-lived 3MLCT state phosphorescence gives these systems potential application as biological imaging agents, with the variance in N^N ligand allowing for various localisation points in a cell. The photophysical effect of changing the N^N ligand is also investigated with the subsequent effects on the Stern-Volmer constant. The penta-triazole and Bphen-containing complexes were revealed to have the highest sensitivity towards 3O2. Preliminary studies on healthy and cancerous cell lines were also conducted. Whilst limited detail from the biological data can be taken due to the study being in its preliminary stages, some complexes were observed to stand out. Namely [Os(bpy)2(btz)][Cl]2 was observed to display the largest selectivity indexes of 14.91 and 19.30 on RT112 and EJ138 cancerous cell lines and also displayed non-toxicity on the healthy cell line (IC50 - 281 µM) making it ideal for use in biological applications. Other complexes also display appreciative selectivity towards some of the cancer lines. [Os(TAP)2(dppz)][Cl]2 was also observed to display notable biological data displaying red emission while localised in the nuclear envelope. Studies also illustrated intercalation via the dppz ligand, with a TAP unit sitting in a groove. The preliminary studies display how these complexes have potential use as PDT/PACT/biological imaging agents.
| Date of Award | 6 Jun 2023 |
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| Original language | English |
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| Supervisor | Paul Elliott (Main Supervisor) & Roger Phillips (Co-Supervisor) |
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