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Construction of template-assembled pyrimidine-based quartets and quadruplexes

University of British Columbia

Pyrimidine-based quartets and quadruplexes are unstable and thus are rarely encountered in nature. Uracil (U) and thymine (T) quartets in the solution state have only been found as part of pre-existing G-quadruplex scaffolds and the corresponding quadruplexes have not been reported. Studies on such systems might shed light on their role in nucleic acid topology and stability. This thesis describes the assembly and structural characterization of these motifs in vitro as a result of grafting the respective nucleosides onto resorcinol-based cavitands. These rigid macrocycles serve as molecular templates on which these motifs are preorganized. Reduction of entropic loss improves thermodynamic stability and promotes self-assembly. A convergent synthetic strategy was employed for accessing these cavitand-nucleoside conjugates. Cavitands and nucleosides were prepared separately using established literature methods, and the final coupling step of the two components entailed a copper (I)-catalyzed azide-alkyne cycloaddition, or a "click" reaction. NMR spectroscopy was used extensively in signal assignment, structure elucidation and oligomeric state analysis. CD spectroscopy was employed in some cases to provide further confirmation of defined structure. Findings indicated the spontaneous self-assembly of a U-quartet in CDCl3 at both 25 ºC and –20 ºC. In the presence of a metal cation (Sr²⁺), symmetric homodimerization of two U-quartets occurs at 25 ºC. The corresponding U-quadruplex unit was identified in DMSO-d₆ at 25 ºC. The T-quartet was shown to be nonexistent at 25 ºC, but assembles at a low temperature of –40 ºC. iii No evidence for metal cation uptake was found at 25 ºC. Assembly of the T-quadruplex was confirmed in DMSO-d₆ at 25 ºC. In all of these systems, stacking of the nucleobase and triazole linker rings was indicated suggesting π-stacking interactions to be a significant contributor to overall stability.

Text

2014-07-17

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/48391

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/