Photochemical Sciences Ph.D. Dissertations

Oxidation of nucleic acids: Chemistry of pyrene quinone and development of dihydrodioxins as DNA photooxidizing agents.

Date of Award

2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Photochemical Sciences

First Advisor

R. Marshall Wilson (Advisor)

Second Advisor

Farida Selim (Other)

Third Advisor

H. Peter Lu (Committee Member)

Fourth Advisor

Andrew T. Torelli (Committee Member)

Abstract

Pyrene-4,5-dione (pyrenequinone) is a polycyclic aromatic hydrocarbon (PAH) a planar group and DNA-cutting functionality that can cause cytotoxic, mutagenic, and carcinogenic damage to DNA and can encourage cancers in humans. It is extensively accepted that PAHs require metabolic activation in order to exert their biological activities, including carcinogenicity. Upon entering the cell PAHs are either metabolized into diol epoxides, quinones, or free-radical intermediates, all of which can react with cellular DNA to produce PAH-DNA covalent adducts and cause other forms of DNA damage. We have studied the binding and photo-reaction of pyrenequinone without masking with herring sperm (HS) DNA in order to see if it binds or not. Pyrenequinone does not bind to herring sperm DNA but it can form hydrogen bonds with bases. In addition, pyrenequinone does not linearized super coiled FX174 plasmid DNA by itself without a masking group. We attribute this to the low solubility of pyrenequinone in water, since when it masked with a water solubility group, it is very effective in causing DNA damage. Electrochemistry results suggest that reduction potentials of first electron denoted to pyrenequinone in acetonitrile has E0red= -0.052V vs NHE, and to semiquinone radical anion. Thus, the Gibbs free energy (¿G0) of the electron transfer to pyrenequinone in DNA was roughly estimated using Rehm–Weller equation. The estimated value of ¿G0 (¿G0= -33.536 Kcal/mol) indicates the electron transfer can happen spontaneously from adenine to the photoexcited PQ. These results strongly suggest, and are consistent with the hypothesis, that the pyrenequinone cleaves and /or damages DNA duplexes at Gs or As when it is intercalated between base pairs and has preferable binding to GG or AA DNA sites. However, the very low quantum yield of pyrenequinone release from N,N-10,11-dimethylpyridinium PDHD+2-2BF4- (PDHD) (¿=1.703*10-4) and transient absorption decay studies provide information about the mechanism of pyrenequinone photochemical release from PDHD. In order to increase the yield of pyrenequinone release from PDHD, we designed an experiment to facilitate pyrenequinone release from PDHD, which has autocatalytic behavior in the presence of pyrenequinone using visible light 445 nm. Evaluation of DNA-PDHD interactions has been investigated by mass spectroscopy electrospray ionization. In this work, experiments using DNA with known sequences of nucleotides such as: A7+ PDHD, A7+ PQ, ds (A7T7) +PDHD, and ds (A7T7) +PQ, were investigations. PDHD+2-2BF4- photochemically damages the DNA and the generated pyrenequinone and dipyridinum stilbene become attached to the DNA bases in different positions.

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