[-] Show simple item record

dc.contributor.advisorGates, Kent S. (Kent Stephen), 1962-eng
dc.contributor.authorSarkar, Ujjal, 1979-eng
dc.date.issued2009eng
dc.date.submitted2009 Falleng
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.descriptionTitle from PDF of title page (University of Missouri--Columbia, viewed on January 28, 2011).eng
dc.descriptionThesis advisor: Dr. Kent S. Gates.eng
dc.descriptionVita.eng
dc.descriptionIncludes bibliographical references.eng
dc.descriptionPh. D. University of Missouri--Columbia 2009.eng
dc.descriptionDissertations, Academic -- University of Missouri--Columbia -- Chemistry.eng
dc.description.abstractTirapazamine (TPZ) is currently undergoing a variety of phase I, II, and III clinical trials for the treatment of various human cancers. TPZ derives its medicinal activity by inducing DNA damage in poorly oxygenated tumor cells. Selective bioreductive enzymatic metabolism of TPZ in tumor cells leads to radical intermediates, which primarily contribute oxidative DNA damage. The nature of radical intermediates responsible for DNA damage is still a matter of debate. At the same time, there is an ongoing effort to prepare TPZ analogues as potential new antitumor agents. Thus, there is immediate need for the development of synthetic methods for the preparation of TPZ analogues. The very first part of this dissertation provides the utility of Suzuki coupling in the synthesis of 3-alkyl and 3-aryl derivatives of the antitumor agent TPZ. In these studies, the bromo substrate provided improved yields that chloro. To the best of our knowledge, we have provided general scope of Suzuki coupling reaction on the benzotriazine-1-oxide substrates involving various 3-aryl, and 3-cyclopropyl boronic acid to build a series of TPZ analogues. In addition to this work, we prepared novel 3-cyclopropyl-1,2,4-benzotriazine 1,4- dioxide which damages DNA under bioreductive hypoxic conditions. We also, utilized another 3-alkyl derivative of TPZ, 3-methyl-1,2,4-benzotriazine-di-N-oxide, to reinvestigate the mechanism of TPZ action. Our data imply the release of hydroxyl radical from activated TPZ is a reasonable mechanism to explain the DNA damage. This information is critical to our understanding of the effect of anticancer agent TPZ on various solid tumors We also show for the first time that other class of heterocyclic N-oxides such as natural product myxin and methylmyxin behave like redox activated hypoxia selective DNA damaging agent tirapazamine. In the last part of this thesis, we have explored for the first time the chemistry of the benzotriazine scaffold as a hypoxia-selective fluorescent probe. We have studied with a series of known benzotriazine compounds, and have found a few with a moderate fluorescence quantum yield and molar extinction coefficient. Our novel effort toward hypoxia directed fluorescent small molecule probes may be useful for imaging in cancer therapy, and other hypoxia related diseases.eng
dc.format.extentxviii, 152 pageseng
dc.identifier.oclc698689052eng
dc.identifier.urihttps://hdl.handle.net/10355/9876
dc.identifier.urihttps://doi.org/10.32469/10355/9876eng
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartof2009 Freely available dissertations (MU)eng
dc.relation.ispartofcommunityUniversity of Missouri-Columbia. Graduate School. Theses and Dissertations. Dissertations. 2009 Dissertationseng
dc.subject.lcshCancer -- Treatmenteng
dc.subject.lcshHeterocyclic compoundseng
dc.subject.lcshNitrogen oxideseng
dc.titleMetabolically activated heterocyclic N-oxide compounds for killing and visualizing hypoxic cancer cellseng
dc.typeThesiseng
thesis.degree.disciplineChemistry (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


Files in this item

[PDF]
[PDF]
[PDF]

This item appears in the following Collection(s)

[-] Show simple item record