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Title page for ETD etd-03252013-221609


Type of Document Dissertation
Author Ketron, Adam Christopher
URN etd-03252013-221609
Title Synthetic and Natural Products as Poisons of Human Topoisomerase II
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Michael Stone Committee Chair
Charles Sanders Committee Member
Daniel Liebler Committee Member
Martin Egli Committee Member
Neil Osheroff Committee Member
Keywords
  • DNA topology
  • DNA intercalation
  • oxidative metabolism
  • Phillyrea latifolia
  • drug-DNA interactions
Date of Defense 2013-02-08
Availability unrestricted
Abstract
The topological structure of DNA is regulated by ubiquitous enzymes called topoisomerases. Type II topoisomerases resolve supercoils and remove knots and tangles from the genetic material by generating transient breaks in the DNA backbone. Despite the essential nature of these enzymes in cellular physiology, the generation of double-stranded DNA strand breaks gives them the capacity to fragment the genome. This potentially lethal feature of topoisomerase II can be amplified by the presence of compounds (topoisomerase II poisons) that stabilize enzyme-mediated DNA cleavage intermediates, thus converting type II topoisomerases to potent cellular toxins. Structure-activity relationship studies of the intercalative topoisomerase II poison amsacrine indicate that most of the ability of the drug to enhance enzyme-mediated DNA cleavage is embodied in the nonintercalative head group. Simultaneously, the role of the intercalative acridine moiety appears to be to increase the local concentration of the drug at the enzyme-DNA interface. Oxidative metabolites of curcumin, the active component of the spice turmeric, are potent covalent topoisomerase II poisons. Furthermore, a number of novel topoisomerase II poisons are identified from natural sources including thymoquinone, oleuropein, and hydroxytyrosol.
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