Synthesis and characterisation of platinum(II) and ruthenium(II) polyamide conjugates

Abstract

This thesis reports the synthesis and characterisation of two novel metallo-polyamide conjugates; LLSP4-Pt and LLSP4-Ru. Several synthetic strategies were employed in the development of the polyamides, beginning with solution phase chemistry. Construction of the polyamide was attempted via chain elongation with sequential additions of pyrrole monomers, however, solution phase methods were unable to achieve the coupling of four consecutive pyrrole rings. Solid phase chemistry, using a peptide synthesiser, was then used as an alternative. Synthesis using solid phase chemistry required the production of the monomeric building block Fmoc-py-COOH using adaptations of various literature methods and was successfully characterised by 1H NMR. The proof-of-concept molecule LLSP4-DPA was the first polyamide made using Fmoc-I-Alanine-OH-WANG resin although several impurities from the cleaving agent 3-dimethylaminopropylamine persisted despite attempts at purification. The solid phase support was then changed to chlorotrityl resin and was used to synthesise the precursor polyamide LLSP4 with high purity. LLSP4-Pt was then successfully made using chlorotrityl resin and characterised by NMR (1H and 195Pt), ESI-MS and elemental analysis. The ligands dpq, 4-CO2H-phen and intermediates thereof, were successfully synthesised and used in the production of the ruthenium conjugate. The precusor LLSP4-(4-CO2H-phen) was made using the same solid phase techniques employed for LLSP4-Pt. Coordination of [Ru(dpq)2Cl2] to LLSP4-(4-CO2H-phen) was afforded by heating in EtOH producing LLSP4-Ru which was characterised by 1H NMR and ESI-MS. Preliminary studies showed that upon addition of DNA to LLSP4-Ru a large increase in fluorescence is seen which suggests an intercalative binding mode. DNA binding studies for LLSP4-Pt were conducted using CD based titrations with ct-DNA. The binding constant of LLSP4-Pt was found to be 4.1 × 105 M-1 with a binding site size of 4 base pairs. The ability LLSP4-Pt to form coordinate covalent bonds with guanosine nucleosides was investigated and monitored by 1H NMR. Incubation of guanosine with LLSP4-Pt shows a new resonance for H1' is observed at 5.98 ppm while two new resonances for H8 are observed at 8.78 and 8.79 ppm.

Date of Award	2008
Original language	English