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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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
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.
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