dc.contributor.advisor | Gates, Kent S. (Kent Stephen), 1962- | eng |
dc.contributor.author | Abd Elhamed, Mostafa Ibrahem Fekry | eng |
dc.contributor.other | University of Missouri-Columbia. Graduate School. Theses and Dissertations. Dissertations. 2011 Dissertations | eng |
dc.date.issued | 2011 | eng |
dc.date.submitted | 2011 Spring | eng |
dc.description | Title from PDF of title page (University of Missouri--Columbia, viewed on October 22, 2012). | eng |
dc.description | The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. | eng |
dc.description | Dissertation advisor: Prof. Kent S. Gates | eng |
dc.description | Includes bibliographical references. | eng |
dc.description | Vita. | eng |
dc.description | Ph. D. University of Missouri--Columbia 2011. | eng |
dc.description | "April, 2011" | eng |
dc.description.abstract | [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Natural products provide both novel molecular structures and new mechanisms that have significant therapeutical implications. The work described here focuses on elucidating the mechanisms of DNA damage by leinamycin and kinamycin D natural products as well as [alpha]-haloacrolyl containing compounds. Leinamycin is a structurally novel natural product that displays potent activity against human cancer cell lines. Our data reveals that leinamycin alkylates guanine residues in duplex DNA more efficiently than in single-stranded DNA. We estimated the binding constant of activated leinamycin to duplex DNA. The alkylation yields of leinamycin in palindromic sequence DNA and in duplexes containing methylated cytosine residues provide evidence that leinamycin is an atypical DNA-intercalating agent. Agarose gel electrophoresis reveals that kinamycin D natural product can cause DNA damage in presence of glutathione and under hypoxic conditions. The [alpha]-haloacrolyl moiety is found in a variety of cytotoxic natural products. [alpha]-Bromo-2-cyclopentenone was used as a model compound to examine the thiol bioactivation of [alpha]-haloacrolyl-containing molecules. We observed that the reaction between [alpha]-haloacrolyl fragment and different thiols leads to differences in DNA alkylation yields and sequence specificities. This chemical feature may lead to applicable differences in the activity of these agents against several organisms. Both [alpha]-haloacrolyl fragments and leinamycin alkylate DNA. This process leads to formation of abasic sites in the alkylated DNA. We observed that abasic sites in duplex DNA may generate interstrand DNA crosslinks under biologically-relevant conditions. Interstrand crosslinks present a challenge to cellular DNA repair systems, and the repair of these lesions can be mutagenic. | eng |
dc.format.extent | xiv, 144 pages | eng |
dc.identifier.oclc | 872563648 | eng |
dc.identifier.uri | https://doi.org/10.32469/10355/15824 | eng |
dc.identifier.uri | https://hdl.handle.net/10355/15824 | |
dc.language | English | eng |
dc.publisher | University of Missouri--Columbia | eng |
dc.relation.ispartofcommunity | University of Missouri--Columbia. Graduate School. Theses and Dissertations | eng |
dc.rights | Access is limited to the campuses of the University of Missouri. | eng |
dc.subject | DNA-intercalating agent | eng |
dc.subject | abasic site | eng |
dc.subject | mutagenics | eng |
dc.subject | leinamycin | eng |
dc.subject | kinamycin D | eng |
dc.title | Chemical mechanisms of DNA damaging natural products | eng |
dc.type | Thesis | eng |
thesis.degree.discipline | Chemistry (MU) | eng |
thesis.degree.grantor | University of Missouri--Columbia | eng |
thesis.degree.level | Doctoral | eng |
thesis.degree.name | Ph. D. | eng |