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The structural chemistry of fluorinated nucleic acid components and possible implications for fluorinated DNA self-assembly

Boyle, Bryan (2012) The structural chemistry of fluorinated nucleic acid components and possible implications for fluorinated DNA self-assembly. PhD thesis, University of Glasgow.

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Abstract

The main focus of this project has been the investigations into the effect that fluorine substitution has on structures of molecular complexes containing DNA base molecules. Previous work done on these molecules has been targeted at producing anti-cancer or antiviral treatments, which reflects an important ultimate aim of investigations in this area. Success in this structural project would make a contribution towards this aim, by helping the understanding of the effects of fluorination on some of the interactions that control DNA self-assembly, notably base-pairing and stacking interactions, together with additional interactions involving fluorine. The specific aim of this project was to grow crystals of molecular complexes of cytosine and 5-fluorocytosine with co-molecules and use the structural descriptions to assess the difference between the structures and the influence the presence of the fluorine atom has on the structure when compared to the nonfluorinated equivalent. Single crystal X-ray diffraction has been the main method of analysis, backed up by related techniques. Many crystallisations have been set up with cytosine and 5-fluorocytosine with a wide range of targeted co-molecules. 5-fluorouracil and uracil have also been used in related co-crystallisations with the aim of producing related complexes of these materials with the same co-molecules as used with cytosine and 5-fluorocytosine. In both families of complexes it was hoped that the fluorine would have an effect on the base-pairing motifs adopted in the structures, with the control being the non-fluorinated structure. The program dSNAP has been used to give a comparison of the structures produced in this work with those already reported in the CSD. This program has given an indication of the classification of the standard primary bonding motifs and to analyse the other features commonly seen in base pairs such as buckling and propeller twisting. The comprehensive series of complexes produced have provided the opportunity to examine significant structural trends, notable in the adoption of various base-pair motifs based on the Watson-Crick, Hoogsten and derived base-pairing patterns. The degree of proton transfer to the ring nitrogen of the cytosine could be rationalised in terms of the DpKa values, and the proton transfer has a substantial effect on the base-pair motifs able to be adopted. The classification of the complex structures in terms of hetero (pseudo)-basepairing has also been found to be of value. Extensive base-stacking and weaker interactions involving fluorine are also present; these have been analysed and found to have significant effects on the structures adopted, and hence may have future implications for the assembly of fluorinated DNA.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Wilson, Prof. Chick
Date of Award: 2012
Depositing User: Mr Bryan Boyle
Unique ID: glathesis:2012-3198
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 29 Feb 2012
Last Modified: 10 Dec 2012 14:05
URI: http://theses.gla.ac.uk/id/eprint/3198

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