Theses and Dissertations

Issuing Body

Mississippi State University

Advisor

Lewis, Edwin A.

Committee Member

Fitzkee, Nicholas C.

Committee Member

Wipf, David O.

Committee Member

Zhang, Dongmao

Committee Member

Emerson, Joseph P.

Date of Degree

12-8-2017

Document Type

Dissertation - Open Access

Major

Chemistry

Degree Name

Doctor of Philosophy (Ph.D)

College

College of Arts and Sciences

Department

Department of Chemistry

Abstract

Cancer results from the accumulation of genetic mutations in a normal cell that ultimately result in the expression (or overexpression) of oncogenes. The design of drugs having high affinity for specific DNA sequences or structural motifs is vital to gaining a better understanding of gene expression and to the development of new cancer treatments that are based on turning off oncogene expression. This dissertation presents studies of the binding of two ligand families, Berenil (DMZ), and ruthenium polypyridyl complexes (RPCs), to B-DNA and G-quadruplex (G4) DNA. The structureunction relationships for the interaction of these ligand families with DNA were probed by functional group substitution, truncation, or modification of the DMZ amidine groups, and by changing one of the RPC ruthenium ligands from phenanthroline to dipyridophenazine (dppz) or tetraazatetrapyrido-pentacene (tatpp), and lastly by adding a second Ru(Phen)2 core to the tatpp bridging ligand. Removal of one or both amidine groups from DMZ drastically reduces its binding to both B-DNA and G4-DNA. DMZ analogs in which one amidine was replaced by an alkyne group were synthesized with the expectation that the additional π-bonding character of the alkyne group would increase G4 affinity. All of the DMZ alkyne compounds were found to bind preferentially to G4-DNA (over B-DNA) and a few of these compounds demonstrated significant anticancer activity. RPCs with progressively longer ruthenium bound ligands were found to bind with differing affinities to B-DNA and G4-DNA. Monoruthenium RPCs exhibited a preference for binding to B-DNA, while binding the diruthenium RPC to G4-DNA was more complicated exhibiting both tighter and a weaker binding modes in comparison to the B-DNA complex. The diruthenium complex was found to bind more tightly to G4-DNA by approximately 3 kcal mol-1. The binding of small molecules to DNA resulting in the disruption of oncogene transcription represents a powerful approach to the treatment of cancer.

URI

https://hdl.handle.net/11668/20301

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