The aim of this project was to develop a model for prediction of bioavailability of drug compounds from structural features. Literature bioavailability data was gathered for over 700 compounds. This data was evaluated and assigned a quality score. Prodrugs and drugs known to be actively transported were excluded from the dataset. The factors that affect bioavailability include solubility, permeability and first-pass metabolism. Each of these factors was considered. The first stage was to develop a model to predict solubility and to study the effects of pH on solubility. Solubility was measured in water for a set of 99 compounds selected from the bioavailability dataset, using HPLC as the analytical method. Solubility was also measured in simulated gastric fluid, SGF (pH 1.2), and simulated intestinal fluid (fed state and fasted state), FeSSIF and FaSSIF at pH 6.5. An equation for change in solubility with pH was shown to perform quite well. An Abraham equation was developed to account for solubility enhancement due to the presence of micelles in simulated intestinal fluid. Abraham equations were derived for prediction of diffusion in water and in ethanol using literature data. Diffusion in ethanol was predicted best and was used in place of permeability to classify the bioavailability data according to the Biopharmaceutics Classification System. A compound which is highly metabolised will have low bioavailability. Human plasma clearance data was used as a measure of the degree of metabolism of a drug. A molecular fragment-based approach using PLS statistics was used to develop a model of human plasma clearance of drugs for over 400 drugs. The final stage of this work was to develop a model of bioavailability. The best model used PLS statistics and included chain-based molecular fragments in combination with calculated aqueous solubility, diffusion coefficients (in ethanol) and plasma clearance.

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Streptonigrin has shown activity against several tumours (e.g. breast and lung). The drug induces cytotoxicity by impairing DNA synthesis via inhibition of Topoisomerase II and direct damage to DNA through attack by ROS (reactive oxygen species), the latter of which has been linked to the aminoquinone domain [Bolzc'm and Bianchi 2001]. Streptonigrin exists in one of three possible oxidation states, the oxidised quinone, the le- reduced semiquinone radical and a 2e- reduced hydroquinone. The semiquinone radical has been linked to the production of ROS species through redox cycling in the presence of oxygen. The superoxide and hydroxyl radicals cause damage to various cellular constituents e.g. proteins and nucleic acids (HO· is the primary source of the drug's toxicity). In addition to this streptonigrin has a high affinity for different metal ions e.g. iron and copper. The drug-metal complexes are known to increase streptonigrin's binding affinity to DNA [Bolzfm and Bianchi 2001]. Little is known about the effects of the metal on the chemical and biological activity of the drug. Most of the research on the redox chemistry of streptonigrin (SN) has consisted of NMR studies of SN metal complexes in organic solvents at concentrations which are not feasible at physiological conditions. This research focused on determining the precise mechanism involved in streptonigrin semiquinone formation; the precise role of different metal ions in semiquinone formation and the affect of different pH via two buffers with different pHs (5.5 and 9.5). The experimental data showed that semiquinone formation occurred via complete reduction followed by oxidation rather than I e- reduction . Subsequent EPR experiments also confirmed that metal ions had a direct affect on semlqumone formatIon, wuh streptol1lgrm metal bmdmg ratios greater than I: I mhlbumg semiquinone formation. Experiments carried out to measure reactive oxygen species formation by the drug showed limited evidence of superoxide formation by the different drug metal complexes; however there was clear evidence of hydroxyl radical formation which appeared to change in concentration with metal ion concentration in a similar fashion to the semiquinone. The experimental work should assist future drug analogue development.

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