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Synthesis of nucleic acid-binding ligands

Alaboosh, Jamal 2017. Synthesis of nucleic acid-binding ligands. PhD Thesis, Cardiff University.
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Abstract

The most favoured amino acid in protein-nucleic acid interfaces is arginine due to the existence of the guanidinium group in its structure that can form good hydrogen-bonding geometries. In addition, the length of the side chain gives it a great deal of torsional freedom and therefore permits the guanidinium group to orient itself to interact with a wide range of targets through bidentate H-bonding. A torsional constraint for the guanidine group could be achieved by its conversion into a bicyclic framework, resulting in unidirectional hydrogen bonding with its targets and reducing the loss of the conformational entropy as a result of its binding. The aim of this research is to synthesise nucleic acid targeting oligopeptides which will include non-natural analogues of arginine as part of their sequence with the purpose of activating or inhibiting biological functions. The synthesis of different sized rings of bicyclic guanidine derivatives could be a means to control the hydrophobic interaction with DNA, with hydrophobicity increasing as the size of the ring of the bicyclic guanidine increases. In addition, the high basicity of guanidine leads to production of the corresponding guanidinium cation upon protonation. Therefore, the formation of guanidinium cation leads to hydrogen bonding and electrostatic interactions with anions like phosphate groups. So, the purpose of preparing differently sized rings of bicyclic guanidine in the current work is to compare their interactions with DNA. There are four themes in our research concerned with the design and synthesis of bicyclic guanidine derivatives and non-natural amino acids. The first theme concerns the synthesis of a protected bicyclic guanidine methylene amine that was achieved by utilising Boc-L-methioninol as a precursor and converting it to the corresponding azide. However, incorporation of this bicyclic guanidine into an amino acid moiety proved difficult and thus themodified amino acid was not formed. The second theme of the project considers a novel strategy to generate a bicyclic guanidine methylene alcohol with a variably sized ring in a high yield starting from an azido alkane amine and Boc-L-methionine as precursors. This modification to the route will open a promising way to produce the functionalised bicyclic guanidine. Bicyclic guanidine methylene chloride was synthesised that gave us a way to insert bicyclic guanidine into a tyrosine amino acid moiety so that a protected L-tyrosine possessing bicyclic guanidine with a differently sized ring could be synthesised. The third theme involved the new strategy towards the synthesis of bicyclic guanidine methylene amine followed by conjugation with Fmoc-Glu-OAll to produce a modified amino acid. The fourth, and final,theme of our research includes the preparation of dimers of bicyclic guanidine. Furthermore,a crystal structure for the protected bicyclic guanidine intermediate in this theme has also been obtained.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 7 November 2017
Last Modified: 17 Oct 2019 02:36
URI: http://orca-mwe.cf.ac.uk/id/eprint/106299

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