Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Committee Member

Dr. Dev P. Arya, Committee Chair

Committee Member

Dr. R. Karl Dieter

Committee Member

Dr. Jeffrety T. Petty

Committee Member

Dr. Daniel C. Whitehead

Abstract

Small molecules have provided means to combat many diseases caused by pathogens. In the last six decades, advances in the structural and biological understanding of nucleic acid functions have led to rational drug design programs in order to solve current therapeutic challenges. The work described in this dissertation addresses discovery of aminoglycosides as novel binders to G-quadruplex nucleic acids. Understanding of effect of linker length on the B-DNA binding of a series of Hoechst 33258 derivatives have been provided. Novel Hoechst 33258 based monobenzimidazoles have been synthesized and their biological properties have been compared with the bisbenzimidazoles. The bisbenzimidazoles have been designed to be useful towards click chemistry applications. These clickable Hoechst 33258 derivatives were then used to prepare neomycin-Hoechst 33258 conjugates with varied linker spacing between them. The binding studies of these novel neomycin-Hoechst 33258 conjugates show intercalative binding of bisbenzimidazole moiety of the ligand to an RNA duplex. Finally, the novel neomycin-Hoechst 33258 conjugates have been screened against G-quadruplex forming promoter sequences and biophysical characterization to its binding has been provided. Overall, these studies have led to synthesis of novel small molecules that bind to various nucleic acids and their new binding modes have been discovered. The studies presented here are expected to help in the design of novel therapeutics.

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