UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthesis of template-assembled nucleotide quartets Bare, Grant


The thesis work described herein addresses a desire to isolate a guanine quartet and other unknown nucleobase quartets in Nature's solvent, water. Template-assembly of the nucleobase quartets or tetrads by the application of a cavitand template molecule was utilized as a synthetic strategy. Several synthetic precedents were sought and included developing DNA synthetic methodologies for four-fold nucleotide coupling of deoxyguanosine onto an individual substrate, imparting solubility in water on the resultant supramolecular constructs, and designing molecules capable of stabilizing G-quartet or G-tetrad self-assemblies. Chapter 1 forms an introduction for this work by summarizing significant reports in the scientific literature on nucleic acid structure and function and on known template-assembled syntheses of nucleic acid elements. Chapter 2 describes the development of phosphite triester and phosphoramidite DNA synthetic methodologies for synthesizing water-soluble phosphate-linked cavitand-nucleotide conjugates. The synthesis of triazole-linked cavitand-guanosine conjugates with imparted water-solubility is dealt with in Chapter 3. In Chapter 4, evidence is provided for the observation of unimolecular cation-free template-assembled guanine and thymine quartets in methanol solvent using the phosphate-linked architecture. Finally, Chapter 5 describes the first potential isolation of a single G-tetrad in water through template-assembly directed by a phosphate-linked cavitand-nucleotide conjugate. This species is shown to interact with small molecule binders of G-quadruplex DNA and inhibitors of the human telomerase enzyme. The novel supramolecules synthesized in this thesis have been shown to assist in the discovery of unusual DNA based structures, to act as a minimal model of human telomeric G-quadruplex DNA, and to serve as artificial receptors for potential anticancer therapeutics.

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