The chemistry of complex ion anti-tumour agents

Abstract

Reported here is a study of the solution chemistry of the anti-cancer drug cis-dichloro-diammineplatinum(II), cis-[PtCl₂(NH₃)₂]. In view of uncertainties in literature values of rate constants and in reaction conditions for the reactions of cis-[PtCl₂(NH₃)₂], the kinetics of the first acid hydrolysis step of cis-[PtCl₂(NH₃)₂] are reinvestigated in HClO₄ media, as well as the kinetics of the second hydrolysis step. All the kinetic investigations in this thesis are made using a DMS100 UV - visible spectrophotometer, using the changes in absorbance to monitor reactions.

The nature and rate constants for the hydrolysis of cis-[PtCl₂(NH₃)₂] and the anation kinetics of the products under a variety of pH and ionic strength conditions are investigated, such as the kinetics of the base hydrolysis of cis-[PtCl₂(NH₃)₂] and its rates of hydrolysis over a wide pH range. The kinetics of the reactions of some of these hydrolysis products with a variety of ligands, some physiologically relevant and some not, such as chloride ions, sodium hydrogen malonate, glycine and ortho-phenylenediamine, are also investigated. In order to model the situation in vivo as closely as possible, a technique involving the combination of the UV - visible spectrophotometer with a pH-stat is used extensively. This enables the pH to be kept constant while a reaction in progress is being monitored. The likely distribution of platinum(II) species present in blood plasma and inside a cell is thus calculated as a result of these investigations.

A possible role for metal ions in accelerating both the acid and base hydrolyses of cis-[PtCl₂(NH₃)₂] is investigated, although metal ions found in vivo are found to have no effect. The crystal structure of the product of the reaction between cis-[PtCl₂(NH₃)₂] and HgCl₂ is reported. The effect of mixtures of aqueous and non-aqueous solvents on the rate of hydrolysis of cis-[PtCl₂(NH₃)₂] was investigated as well as the kinetics of the first acid hydrolysis step of cis-[PtBr₂(NH₃)₂] and the bromide anation of cis [PtBr(NH₃)₂(OH₂)]+.

As a result of this experimental work, attempts were made to extrapolate the results of these kinetic investigations, all carried out under stringent reaction conditions, to the possible reactions of cis-[PtCl₂(NH₃)₂] in vivo.