Dougherty, Geoffrey (1979) Quantitative: microspectroscopic studies of DNA-drug complexes. Doctoral thesis, Keele University.

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Abstract

The interactions in solution and in.the fibre state of the trypanocidal phenanthridine drugs, ethidium bromide, dimidiura bromide and prothidium (di)bromide with DNA have been investigated using a variety of physical techniques. A number of analytical techniques applicable to polymer-ligand interactions have been developed and used in the analysis of these results.
For each of the drugs, complexes were prepared with three natural DNA's of different nucleotide compositions using a novel mixing scheme.
The solution spectra were analysed in terms of binding affinity, number and size of binding sites and base-pair specificity. The binding of ethidium and dimidium is limited by neighbour exclusion effects, whilst prot’adium is able to bind to higher levels.
Fibre X-ray diffraction showed that dimidium and ethidium caused a substantial increase in the DNA pitch at high humidities, probably through intercalative binding. In contrast, the binding of prothidium appears to cause no change in the DNA secondary structure at any humidity. The birefringence and linear dichroism of the fibres used in the diffraction study were measured over a range of humidities, using a microspectrophotometer. The results are interpreted in terms of the tilt angle of the base-pairs and/or drug chromophores, the disorientation of the DNA helices (estimated from the diffraction patterns) and the fractions of bound drug. At high humidities, a substantial fraction of ethidium or dimidium is oriented perpendicular to the helix axis, consistent with intercalation. The X-ray diffraction and dichroism measurements considered together give an unwinding angle at the intercalation site of about 34°. This is unexpectedly large but there are difficulties in combining the results from these two techniques. Prothidium shows little preferred orientation in its binding. A combined external binding scheme is p’^esented with some molecules inclined parallel to the sugar-phosphate chain, and others binding across adjacent chains. Computer drawings and molecular models illustrate these suggested binding schemes.

Item Type: Thesis (Doctoral)
Subjects: Q Science > QC Physics
Divisions: Faculty of Natural Sciences > School of Chemical and Physical Sciences
Contributors: Pigram, WJ (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 30 Sep 2019 15:49
Last Modified: 30 Sep 2019 15:49
URI: http://eprints.keele.ac.uk/id/eprint/6907

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