Synthesis of multi-modal metallodrugs as anti-cancer agents

Thesis

Since the serendipitous discovery of Cisplatin in 1965, innumerable platinum-based derivatives have been explored as alternative anti-cancer agents. In the scope of this research, [2+3]-cycloaddition reactions between diazidoplatinum(II) complexes and gold(I) alkynes were utilised for the synthesis of functionalised multi-modal platinum(II)-gold(I) complexes. The rationale of ligand design was based on literature reports as well as theoretical investigations of the frontier orbitals of potential candidates. With the aim of expanding the historic focus on N-donor ligands, P-donor ligands in the form of substituted phosphines were chosen on the platinum centre. In addition, complexes with both N- and P-functionalities within the ligands were pursued in order to identify electronic trends. The readiness of the diazidoplatinum(II) complexes towards the cycloaddition reaction was correlated to the electronic configuration of the platinum centres via 195Pt NMR spectroscopy. The complexes were characterised via NMR, IR and UV-visible spectroscopy, along with mass spectrometry. Various molecular structures in the solid state were confirmed by means of X-ray diffractometry. Attempted development of the platinum(II) complexes as candidates for platinum(IV) prodrugs via oxidation were unsuccessful.

Four of the synthesised complexes were investigated regarding their photosensitising and radiosensitising properties following the irradiation with blue or green light, and X-rays. In most cases, irradiation of the bimetallic complexes led to bond cleavage and breakdown of the compounds. Cytotoxicity studies were performed on three cancer cell lines with and without irradiation under X-rays and the results were compared to those of Cisplatin. No clear indication of radiosensitising properties were observed, however, cytotoxicity was enhanced by the combination of the two metal complexes. Further in-depth investigations are required in order to draw final conclusions on the reproducibility and the activation of the cytotoxic properties of the complexes following irradiation.

Authors: von Randow, CA

• DOI: 10.5287/ora-bezbpgzbz
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: platinum; iclick; radiosensitivity; cycloaddition reaction; cyclotoxicity; anti-cancer agent
• Subjects: Inorganic compounds; Chemistry, Inorganic; Bioinorganic chemistry