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dc.contributor.authorClement, Jason Andersonen_US
dc.date.accessioned2014-03-14T20:19:38Z
dc.date.available2014-03-14T20:19:38Z
dc.date.issued2005-11-16en_US
dc.identifier.otheretd-12022005-160735en_US
dc.identifier.urihttp://hdl.handle.net/10919/29879
dc.description.abstractAn extract of the sponge Rhabdastrella globostellifera was active in an assay measuring stabilization of the binding of DNA with DNA polymerase β. From this extract, four isomalabaricane triterpenoids were isolated and characterized, three of which were active in the binding assay. All compounds were active in the A2780 ovarian cancer cell line assay. Bioassay-guided fractionation of an extract of a sponge of species Dysidea using the A2780 bioassay yielded the known scalarane sesterterpenoid heteronemin in good yield. Four derivatives of heteronemin were prepared semisynthetically from the natural product, tested for their bioactivity, and their structure-activity dependence was observed. Bioassay guided-fractionation of an extract of a Tuemoya sp. green alga, using an assay for inhibitors of the enzyme Tie2 kinase, afforded a two sulfated cycloartanol triterpenoids. Both the major and minor compounds were identified by spectroscopic methods. Bioassay-guided fractionation of an extract of Petalonyx parryi yielded three known oleanane triterpenoids which inhibited the lyase domain of DNA polymerase β. The structures were confirmed by NMR spectroscopic techniques. This is the first reported study of the chemical components of Petalonyx parryi. As part of our antitumor natural product drug discovery efforts, several extracts were selected for bioassay-guided fractionation based on their activity in initial in vitro screens. A new dereplication method using aminopropyl SPE cartridges was applied to six of these extracts, and four of the extracts were dropped due to the presence of long-chain fatty acids (LCFAs). We present results for the testing and application of this SPE-based method for LCFA dereplication. The cell cycle kinase Chk1 is an interesting target for the development of agents which might potentiate DNA damaging agents. Typical assays for Chk1 involve the use of expensive or radioactive reagents. To facilitate the development of new assays using shorter peptide substrates, small libraries of peptides have been synthesized and tested for their activity as Chk1 substrates. Several of the substrates synthesized displayed activity in the Chk1 assay. en_US
dc.publisherVirginia Techen_US
dc.relation.haspartJACdissertation.pdfen_US
dc.rightsI hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Virginia Tech or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.en_US
dc.subjectsesterterpenoidsen_US
dc.subjecttriterpenoidsen_US
dc.subjectdereplicationen_US
dc.subjectisomalabaricaneen_US
dc.subjectChk1en_US
dc.titleStudies of Bioactive Natural Products and Mechanism-Based Bioassaysen_US
dc.typeDissertationen_US
dc.contributor.departmentChemistryen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineChemistryen_US
dc.contributor.committeechairKingston, David G. I.en_US
dc.contributor.committeememberTanko, James M.en_US
dc.contributor.committeememberDorn, Harry C.en_US
dc.contributor.committeememberCarlier, Paul R.en_US
dc.contributor.committeememberGandour, Richard D.en_US
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-12022005-160735/en_US
dc.date.sdate2005-12-02en_US
dc.date.rdate2005-12-12
dc.date.adate2005-12-12en_US


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