Year of Award

2013

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Medicinal Chemistry

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Nicholas R Natale

Commitee Members

Howard Beall, Michael Braden, Orion Berryman

Keywords

anthracene, anthrone, quadruplex, synthesis, dna, isoxazole

Abstract

Genomic DNA is organized around the double-stranded of B-form DNA, which is both durable and flexible enough to store and pass on genetic information. Once freed from the associations of an extended complimentary sequence, single stranded DNA and RNA can adopt a vast array of stable secondary structure motifs, such as stem-loop, pseudo-knots, and tetra-loops, ideal for its involvement in biological settings other than as a store of genetic information. Originally, alkylating agents were used as "mustard gas" and related chemical weapons in World War I. Alkylating agents, in general, can react with one or two different 7-N-guanine residues and could potentially result in the cross-linkage of DNA strands, preventing uncoiling of the DNA double helix leading to cell death. More recent evidence show that guanine-rich nucleic acids can fold into distinctive four-stranded conformers found in telomeric DNA repeats (i.e. TTAGGG), also known as G-quadruplexes (G4), as well as in sequences in the promoter and other regulatory regions of genes, especially those involved in cellular proliferation. Small molecules that induce the formation of, and selectively bind to, G4 structures are of interest for development as potential anticancer therapeutics. Novel 10-oxoanthracene and substituted anthracenyl isoxazole esters (AIEs) were synthesized and characterized based on NMR studies. To date, quarfloxin is the only G-quadruplex ligand from the large number developed to progress to clinical evaluation. The synthesis, structural characterization, and biological studies will be presented.

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© Copyright 2013 Nathan S. Duncan