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Synthesis of Biologically Active Heterocycles and Development of New Organometallic Methodologies

Arnold, David Matthew (2011) Synthesis of Biologically Active Heterocycles and Development of New Organometallic Methodologies. Master's Thesis, University of Pittsburgh.

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    Abstract

    The study of the synthesis of highly functionalized heterocyclic compounds represents an important subset of synthetic organic transformations leading to target compounds with a wide set of applications in medicinal chemistry, biological chemistry, materials sciences and natural product synthesis. Through this work, synthetic strategies leading to a novel set of ester linked substituted quinoline - uracil scaffolds have been developed and the resulting products were found to be inhibitors of MPK1, an important target in cancer research. This work has also led to the development and implementation of novel synthetic strategies toward highly functionalized, traditionally pharmacologically important 6-amino-, 6-hydroxy- and 6-oxo-uracil and 4,6-dihydroxypiperidone scaffolds. A novel Plk1-PBD inhibitor from this series would be important to probe the mechanism of this enzyme during mitosis and to develop a clinical candidate for this validated cancer target. The Plk1-PBD research endeavor also documents a case for a tandem synthetic/analytical structure determination study. The structure of an initially elusive compound from a high throughput screening of 97,090 compounds was determined by this approach. Finally, the utility of novel heterocyclic sulfonyl and sulfinyl nitrogen protecting groups has been demonstrated through the addition of organometallic reagents to 2-methylthiadiazole-, 2-benzothiazolesulfonylbenzaldimines and 2-pyridylsulfinylbenzaldimines. It was found that these addition reactions proceeded with a variety of organometallic nucleophiles including Gringnard reagents, organozinc and organocuprates. The heterocyclic sulfonyl protecting groups were easily cleaved from the α-branched amines, affording a useful protecting group strategy for the synthesis of this important class of compounds.


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    Details

    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairWipf, Peterpwipf@pitt.edu
    Committee MemberCurran, Dennis Pcurran@pitt.edu
    Committee MemberKoide, Kazunorikoide@pitt.edu
    Title: Synthesis of Biologically Active Heterocycles and Development of New Organometallic Methodologies
    Status: Unpublished
    Abstract: The study of the synthesis of highly functionalized heterocyclic compounds represents an important subset of synthetic organic transformations leading to target compounds with a wide set of applications in medicinal chemistry, biological chemistry, materials sciences and natural product synthesis. Through this work, synthetic strategies leading to a novel set of ester linked substituted quinoline - uracil scaffolds have been developed and the resulting products were found to be inhibitors of MPK1, an important target in cancer research. This work has also led to the development and implementation of novel synthetic strategies toward highly functionalized, traditionally pharmacologically important 6-amino-, 6-hydroxy- and 6-oxo-uracil and 4,6-dihydroxypiperidone scaffolds. A novel Plk1-PBD inhibitor from this series would be important to probe the mechanism of this enzyme during mitosis and to develop a clinical candidate for this validated cancer target. The Plk1-PBD research endeavor also documents a case for a tandem synthetic/analytical structure determination study. The structure of an initially elusive compound from a high throughput screening of 97,090 compounds was determined by this approach. Finally, the utility of novel heterocyclic sulfonyl and sulfinyl nitrogen protecting groups has been demonstrated through the addition of organometallic reagents to 2-methylthiadiazole-, 2-benzothiazolesulfonylbenzaldimines and 2-pyridylsulfinylbenzaldimines. It was found that these addition reactions proceeded with a variety of organometallic nucleophiles including Gringnard reagents, organozinc and organocuprates. The heterocyclic sulfonyl protecting groups were easily cleaved from the α-branched amines, affording a useful protecting group strategy for the synthesis of this important class of compounds.
    Date: 27 January 2011
    Date Type: Completion
    Defense Date: 09 December 2010
    Approval Date: 27 January 2011
    Submission Date: 10 December 2010
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Master's Thesis
    Refereed: Yes
    Degree: MS - Master of Science
    URN: etd-12102010-080955
    Uncontrolled Keywords: anticancer drug target; heterocycle synthesis; imines; inhibitor synthesis; library synthesis; medicinal chemistry; organometallic chemistry; polo-box domain; polo-like kinases; probe development; quinolines; screening artifact; uracils; mitogen-activated protein kinase phosphatases-1; piperidones
    Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
    Date Deposited: 10 Nov 2011 15:10
    Last Modified: 25 May 2012 11:25
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-12102010-080955/, etd-12102010-080955

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