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Small Molecule Biomarkers Resulting from Radiation and Oxidative Damage to DNA

Bhatkhande, Prajakta S
http://orcid.org/0000-0002-0302-4994
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470222983

Abstract Details

2016, Master of Science, University of Toledo, Medicinal Chemistry.
Oxidative damage to DNA and other biomolecules is a result of various reactive radical species that are formed as a result of exogenous factors like radiation or by endogenous mechanisms involving cellular metabolic processes. The role of radiation in direct and indirect DNA damage is a fast growing field of study. Low-energy electrons (LEEs) are a fundamental component of Ionizing Radiation (IR) that are involved in various physicochemical and biochemical phenomena underlying radiation chemistry. This is based on the fact that exposure of biomolecules to such high energy radiation (particles and/or photons) causes electrons to be removed from any atomic or molecular orbitals of the matter accessible at that energy range. These liberated secondary electrons (SEs) can initiate further ionization or excitation processes thus leading to a cascade of events. Two types of radiation induced DNA damage have been studied, direct damage which refers to the direct energy deposition that inflicts damage leading to DNA strand breaks, and the indirect damage which refers to interaction with the molecular environment of DNA, chiefly water, liberating the reactive hydroxyl radical. It has been observed that the addition of LEE to DNA components, triggers the formation of unstable and reactive radicals and ions. These reactive intermediates further generate carbon-centered radicals on the DNA nucleobase as well as the 2-deoxyribose moiety of DNA during the course of DNA damage. Though extensive study has established the importance of nucleobase damage, the oxidation on deoxyribose is also a critical aspect in the toxicology of oxidative stress. DNA damage pathway by LEE involves the cleavage of the phosphodiester bond leading to formation of the C3'-dideoxy and C5'-dideoxy radical at the C3' and C5' positions of deoxyribose. Site selective formation of such radical species through photolysis can be an effective means to study mechanisms involved in their formation and decide their metabolic fate. The goal of this research is to determine the fate of C5'- dideoxy radical by its site selective generation using photolysis. 5'-deoxy-C5' -thymidinyl radical precursor was synthesized using two different organic synthetic approaches and its suitability as a photochemical precursor for generating the 5'-deoxy-C5'-thymidinyl radical was evaluated. Fate of the radical formed can be investigated to develop potential biomarkers for oxidative stress which may in turn be significant towards quantifying the extent and pathogenesis of various diseases. The secondary goal of this research is to synthesize and study the small molecules generated from 3¿-oxonucleotide lesion. The base labile 3¿-oxonucleotide lesion has been observed to undergo nucleobase elimination followed by further degradation to generate 2-methylene-3(2H)-furanone. To fully elucidate the impact of formation of these degradation products on DNA damage and repair processes, it is vital to understand the reactivity and chemical fate of these fragments. Attempts were made to synthesize these small molecule degradation products with focus on 2-methylene-3(2H)-furanone formation.
Amanda Bryant-Friedrich, Ph.D. (Committee Chair)
Paul Erhardt, Ph.D. (Committee Member)
Ezdihar Hassoun, Ph.D. (Committee Member)
137 p.
Biochemistry; Chemistry

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Citations

  • Bhatkhande, P. S. (2016). Small Molecule Biomarkers Resulting from Radiation and Oxidative Damage to DNA [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470222983

    APA Style (7th edition)

  • Bhatkhande, Prajakta. Small Molecule Biomarkers Resulting from Radiation and Oxidative Damage to DNA. 2016. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470222983.

    MLA Style (8th edition)

  • Bhatkhande, Prajakta. "Small Molecule Biomarkers Resulting from Radiation and Oxidative Damage to DNA." Master's thesis, University of Toledo, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470222983

    Chicago Manual of Style (17th edition)

toledo1470222983
401
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This open access ETD is published by University of Toledo and OhioLINK.