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dc.contributor.advisorGates, Kent S. (Kent Stephen), 1962-eng
dc.contributor.authorAbd Elhamed, Mostafa Ibrahem Fekryeng
dc.contributor.otherUniversity of Missouri-Columbia. Graduate School. Theses and Dissertations. Dissertations. 2011 Dissertationseng
dc.date.issued2011eng
dc.date.submitted2011 Springeng
dc.descriptionTitle from PDF of title page (University of Missouri--Columbia, viewed on October 22, 2012).eng
dc.descriptionThe 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.descriptionDissertation advisor: Prof. Kent S. Gateseng
dc.descriptionIncludes bibliographical references.eng
dc.descriptionVita.eng
dc.descriptionPh. 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.extentxiv, 144 pageseng
dc.identifier.oclc872563648eng
dc.identifier.urihttps://doi.org/10.32469/10355/15824eng
dc.identifier.urihttps://hdl.handle.net/10355/15824
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcommunityUniversity of Missouri--Columbia. Graduate School. Theses and Dissertations.eng
dc.rightsAccess is limited to the campuses of the University of Missouri.eng
dc.subjectDNA-intercalating agenteng
dc.subjectabasic siteeng
dc.subjectmutagenicseng
dc.subjectleinamycineng
dc.subjectkinamycin Deng
dc.titleChemical mechanisms of DNA damaging natural productseng
dc.typeThesiseng
thesis.degree.disciplineChemistry (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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