Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

David M. Chenoweth

Abstract

Targeting nucleic acids in a structure- or sequence-specific manner with small molecules remains a significant challenge in chemical biology. The ability to modulate a particular nucleic acid structure would allow for the specific control of cellular processes. Nucleic acid junctions are important structural motifs involved in several biological processes found in DNA and RNA. Three-way junctions (3WJs) occur at replication forks, in triplet repeat expansions, viral genomes, bacterial temperature sensors, as well as riboswitches and building blocks in nanotechnology. We have developed a new class of nucleic acid junction binders based on the small molecule triptycene. These triptycene-based molecules were shown to significantly stabilize a model system junction. After establishing their selectivity towards junctions over other secondary structures, these molecules were applied to biologically relevant junctions. Triptycenes were demonstrated to bind to a d(CAG)•(CTG) repeat implicated in the pathogenesis of triplet repeat expansion diseases, including Huntington’s disease. These molecules may serve as probes to study diseases associated with these repeats. Additionally, we have demonstrated that triptycene-based molecules have the ability to modulate the regulatory region of the rpoH mRNA, involved in the heat shock response in E. coli. These may provide tools to study effects of the heat shock response or as a novel method to target pathogens.The synthesis of large libraries of triptycene molecules would allow for rapid screening of several biologically relevant junctions. We have developed an effective synthesis for bridge-head substituted triptycenes for immobilization on solid support. This allows for the synthesis of these molecules using solid phase synthesis. Triptycene is a scaffold amenable to diversification, allowing for the development of new small molecule probes for the modulation of structure and function of nucleic acid junctions.

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