Identification and characterization of novel oncology related platinum complexes using chromatographic and mass spectrometric techniques

摘要

In this thesis mass spectral and chromatographic techniques were developed and applied to identify and characterise numerous novel platinum(II) and (IV) compounds designed as anticancer agents. In a novel method for the synthesis of cis-oxalato(trans- -1,2- cyclohexanediamine)platinum(II) or oxaliplatin these techniques could be applied to differentiate between the molecular complex and the autoionised analogue (viz. Ptdach2 2+Ptox2 2-). In another novel synthetic method for the same compound the ligand exchange reactions at various temperatures could be investigated and kinetic curves obtained served to illuminate the chemistry involved, indicating the role of small amounts of water in the essentially non-aqueous solvent systems dmf and isoamyl alcohol respectively. These allowed ligand exchange without resulting in hydrolyses even up to 85°C. The ionisation rate of divalent platinum halide complexes was determined for various amine ligands as well as N-S chelate ligands. A comparison of these could suggest why N-S complexes have poor anticancer action. Ionisation was not only studied for neutral molecular species but also for monocationic ones. Relationships could be found with stereochemical aspects of the chelates used. By investigating results of EV-CAD studies thermodynamic data could be obtained which indicated that bond strength decreases from chloro to iodo analogues although extent of ionisation in aqueous solution, i.e kinetic stability, is the reverse. Products formed by the reaction of NO2 gas with Platinum(II) compounds could be identified and separated which greatly contributed to the understanding of the chemistry involved in the formation of mononitro platinum(IV) complexes. Some of these proved to have exceptional anticancer properties. Studies of the interaction of thiol containing biomolecules were performed as a function of time. The results contributed to the understanding of the action of the anticancer agents.