The chemistry of complex ion anti-tumour agents

Type of content
Theses / Dissertations
Publisher's DOI/URI
Thesis discipline
Chemistry
Degree name
Doctor of Philosophy
Publisher
University of Canterbury
Journal Title
Journal ISSN
Volume Title
Language
English
Date
1991
Authors
Miller, Sian Elisabeth
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.

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