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Title: Chemical and Biochemical Redox Reactions of the Anticancer Drug Streptonigrin
Author: Davis, Aaron Vincent Tarn
ISNI:       0000 0004 2677 504X
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2008
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available