The aim of this thesis was the synthesis of gossypol derivatives for biological testing against melanoma and psoriasis. The bis-Schiff s bases of (-)-gossypol and (+ )-gossypol with the following amino acid esters were prepared, isolated, and characterised (yields indicated in brackets); L-phenylalanine methyl ester {( -), 39%; (+), 31 %}, L-tyrosine ethyl ester {(-), 16%; (+), 21%}, L-tryptophan methyl ester {(-), 25%; (+), 25%}, D-tryptophan methyl ester {(-), 24%; (+), 24%}. The half-Schiff's bases of (-)-gossypol and (+ )-gossypol were prepared by the partial hydrolysis of the corresponding bis-Schiff's base; L-phenylalanine methyl ester {( -), 51 %; (+), 13%}, L- tyrosine ethyl ester {( -), 28%; (+), 72%}, L-tryptophan methyl ester {( -), 29%}. An analytical HPLC method was developed for monitoring of these reactions and the determination of the diastereoisomeric purity of the Schiff s bases. The (-)-gossypol and (+)-gossypol enantiomers were prepared in 95% and 91.5% yields by the complete hydrolysis of (-)-gossypol bisel-tyrosine ethyl ester) Schiff's base and (+)-gossypol biseL-phenylalanine methyl ester) Schiff's base, respectively. Racemic gossypolone was prepared in 59% yield by ferric chloride oxidation of gossypol. The synthesis of an individual gossypolone atropisomer was attempted by an oxidative dimerisation reaction, but an unidentified C-C or C-O coupling product was obtained. Two chiral stationary phases were prepared - APS-Hypersil silica coated with CDMPC, and Fluka silica coated with CDMPC. The former was packed into an analytical column, which proved effective for the chiral separation of gossypol atropisomers, but did not give reproducible resolution of the gossypolone atropisomers. Gossypol and some of its derivatives were tested for antipsoriatic activity against a highly proliferating human keratinocyte (HPV -16) cell line, using an MIT viability assay. The most potent inhibitor of psoriatic cell proliferation was (_)_ gossypol (GIso = 5 flM), followed by racemic gossypol, (+)-gossypol, the halfSchiff s bases and racemic gossypolone, with the bis-Schiff s bases being the least active. Gossypol and some of its derivatives were tested as inhibitors of liposomal peroxidation. All compounds tested showed similar antioxidant activity and were more potent than propyl gallate, which was included as an antioxidant standard. Two gossypol half-Schiffs bases were screened for anti-tumour activity against the NCI cell line panel. The most sensitive cell lines to (-)-gossypol half(Lphenylalanine methyl ester) Schiffs base included the melanoma cell lines, SKMEL- 2 and SK-MEL-28, and the most sensitive to (-)-gossypol half(L-tyrosine ethyl ester) Schiffs base included SK-MEL-2. As a result of its activity in the keratinocyte assay, and favourable toxicological profile, gossypol can be regarded as a possible candidate for the treatment of psonaslS. The feasibility of formulating racemic gossypol into a topical preparation was, therefore, investigated. Pre-formulation studies showed; higher gossypol solubility in oily rather than aqueous vehicles, compatibility with commonly used excipients, instability to oxidising conditions, photosensitivity, and preferential partition into organic phases. Racemic gossypol was then formulated into a cream dosage form, which was relatively stable on storage below 40°C, and showed permeation through an artificial membrane in vitro.

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Breast cancer is the most common cancer in women in the UK. Breast screening using mammography imaging is pelformed to detect cancers early and reduce the death rate from breast cancer. It is important that the effect of new imaging technologies on cancer detection is known prior to their use in breast screening. Clinical trials can measure this, however these are expensive and time consuming. In comparison, observer studies with simulated cancers can be performed in a fraction of the time. This thesis focuses on the simulation of calcification clusters and their use in observer studies. Once inserted into breast images the simulated calcification clusters have been shown to look realistic and have the correct contrast and sharpness. " The calcification clusters have been used in observer studies to compare two different types of digital detector - computed radiography (CR) and direct digital (DR) systems, different dose levels and different image processing algorithms. Calcification detection is significantly poorer when using a CR system compared with a DR system, and also sensitive to dose used. It has also been shown that image processing has a significant impact on calcification detection. However, this difference in calcification detection is smaller than the difference in calcification detection due to differences in detector type or dose. Image processing was not found to significantly impact detection of non-calcification cancers. The calcification detection measured using observer studies was compared to the threshold gold thicknesses measured with the CDMAM phantom. Threshold gold thickness was found to be relevant to calcification detection, however the acceptable and achievable threshold limits set in the European quality control protocol using this phantom need revising. The results of this work are important, providing evidence that can be used when selecting the optimal digital detector, dose and image processing.

The study of the correlation between the radiological characteristics of the breast and the likelihood of the breast containing, or subsequently developing, a malignant lesion is termed breast density. In this thesis, a technique is developed for measuring the x-rav attenuation properties of breast tissue from an x-ray mammogram. The measure is independent of the characteristics and configuration of the x-ray equipment used to acquire the image. The intention is to provide a tool which facilitates the study of breast density by providing quantitative measurements of tissue characteristics, which it is hoped will ultimately form the basis of future risk estimation and malignant lesion diagnosis techniques. Part I of the thesis discusses the various area and volumetric measurements of breast density presented in the literature, together with the current hypotheses explaining the statistical results observed in epidemiological studies from a histopathological standpoint. The aim is to develop an inter-disciplinary understanding of the area under investigation to facilitate optimal development. A novel physics based model describing the complete process of mammographic image formation is presented in part II of the thesis. The design, build and test methodology executed for each component of the mammographic equipment is discussed through the chapters: the x-rav tube; the image receptor; and the anti-scatter grid. A ray tracing algorithm for computing the details of traversal paths is presented, as is an algorithm for calculating the scattered energy incident upon the image receptor. In each chapter, the underlying physical model is described, followed by the software design and implementation details, and finally the results of the experimental phantom validations studies to verify the implementation and underlying model. Where appropriate, sensitivity analysis is included so that uncertainty bounds may be estimated. Part III of the thesis proposes a novel measure of breast density, and describes how it overcomes the limitations of many existing techniques, in particular the Highnam and Brady 1996 hint model. The results of a clinical trial are included which demonstrate a favourable correlation between the proposed measure and the occurrence of malignancy compared to that observed using other methods.