Automating the synthesis of platinum(II) complexes and modifying the pharmacokinetics of platinum(IV) complexes

Abstract

New complexes proposed for anticancer treatments hope to mitigate these issues by utilising different mechanisms of action. Polyaromatic platinum complexes are an example of a class of promising new complexes that have a different mechanism of action than the traditional platinum drugs. In this work the method for the synthesis of a series of novel platinum(IV) polyaromatic complexes was developed and these complexes were characterised using ESIMS, UV spectroscopy, CD spectroscopy, SRCD spectroscopy, microanalysis, NMR and HPLC. These complexes were synthesised via the coordination of halides Cl, Br and I in the axial positions producing the di-halogenated platinum(IV) complexes desired. The effectiveness of substitution in the axial position by various ligands was assessed, as well as the cytotoxicity of the resulting compounds in cell lines. It was revealed that these compounds allow the development of new synthetic methods which were previously closed to these complexes, allowing the synthesis of targeted complexes that have the potential to improve prognosis. The developed method is much less time consuming than the current oxidation methods, reducing time spent on synthesising intermediates which will maximise outcomes for further synthesis. The GI50's revealed that these complexes are of comparable cytotoxicity to the platinum(II) complexes and are more cytotoxic than dihydroxido platinum(IV) complexes of the same type. Further development of these complexes was achieved through the linkage of targeting and cytotoxic ligands. These ligands were provided by collaborators and will undergo biological testing in their respective laboratories. DCF, a cytotoxic ligand, was bound in both axial positions through an ethylene diamine linker. The synthesis was confirmed by NMR, providing proof of concept for the attachment of such ligands, further diversifying the skillset of the research group. The PSMA targeting ligand DCL was bound using a succinate linker to one of the axial ligands. This synthesis provided proof of concept for the synthesis of asymmetric compounds with large targeting ligands; whose pharmacokinetics can be further adjusted through derivatisation of the remaining axial ligand. The synthesis of more novel asymmetric complexes was developed, platinum compounds with both a hydroxido and acetardo ligand. The asymmetric design of these compounds will allow further asymmetric derivatisation of the Pt(IV) which may be advantageous in the design and synthesis of multi action drugs.

Date of Award	2018
Original language	English