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Synthesis of dinucleoside tetraphosphates and their analogs
Descriptive
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Title
Synthesis of dinucleoside tetraphosphates and their analogs
Name
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Han
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Qianwei
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Qianwei Han
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author
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Jones
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Roger
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Advisory Committee
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Roger A. Jones
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chair
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Uhrich
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Kathryn
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Advisory Committee
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Kathryn E. Uhrich
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internal member
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Williams
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Lawrence
Affiliation
Advisory Committee
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Lawrence J. Williams
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(authority = RULIB)
internal member
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MacCoss
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Malcolm
Affiliation
Advisory Committee
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Malcolm MacCoss
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outside member
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Rutgers University
Role
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degree grantor
Name
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Graduate School - New Brunswick
Role
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school
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Text
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theses
OriginInfo
DateCreated
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2007
DateOther
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2007
Language
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English
PhysicalDescription
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electronic
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application/pdf
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text/xml
Extent
xiv, 152 pages
Abstract
Dinucleoside polyphosphates, NpnN' (n = 2 - 7), are observed in many biological processes and are recognized as playing important regulatory functions. Ap4A is a particularly important signaling molecule. AZTp4A is the product of excision of AZT by HIV-1 RT from a growing chain of viral DNA, and can be used to study details of the excision process. Its hydrolysis-resistant analogs can be used to study the inhibition of AZT excision. Current methods to prepare dinucleoside tetraphosphates, enzymatic or chemical, are not satisfactory.
A convenient and high-yield method was developed to prepare dinucleoside tetra- and pentaphosphates. The method was based on a mixture of P(III) and P(V) chemistry and involved a trimetaphosphate intermediate. Six dinucleoside tetraphosphates and two pentaphosphates were prepared. In addition, the method was modified to prepare thio, seleno, borano, methylene and difluoromethylene analogs of Ap4A and AZTp4A. These analogs are good model compounds for their unmodified versions. Ap4A analogs can be used to study the mechanisms of its molecular signaling processes. The AZTp4A analogs are currently being used in HIV-1 RT drug resistance studies. The configurations of the diastereomers of the thio, seleno and borano analogs were assigned based on the elution order on reverse-phase HPLC. Enzymatic degradation of the Ap4A analogs was done with snake venom phosphodiesterase in order to confirm the configuration assignments.
Furthermore, this method was extended to prepare multimodified hydrolysis-resistant AZTpSpCX2ppSA and AZTpSpCX2ppSAZT (X = H or F) as potential inhibitors of the AZT excision reaction by HIV-1 RT. The reactions were carried out by the coupling of adenosine or AZT H-phosphonate with trimetaphosphate analogs, taking advantage of the differential power of elemental sulfur to sulfurize H-phosphonate diesters but not monoesters. Enzymatic degradation was performed in order to assign configurations of the diastereomers and compare their enzymatic stabilities.
A convenient and high-yield method was developed to prepare dinucleoside tetra- and pentaphosphates. The method was based on a mixture of P(III) and P(V) chemistry and involved a trimetaphosphate intermediate. Six dinucleoside tetraphosphates and two pentaphosphates were prepared. In addition, the method was modified to prepare thio, seleno, borano, methylene and difluoromethylene analogs of Ap4A and AZTp4A. These analogs are good model compounds for their unmodified versions. Ap4A analogs can be used to study the mechanisms of its molecular signaling processes. The AZTp4A analogs are currently being used in HIV-1 RT drug resistance studies. The configurations of the diastereomers of the thio, seleno and borano analogs were assigned based on the elution order on reverse-phase HPLC. Enzymatic degradation of the Ap4A analogs was done with snake venom phosphodiesterase in order to confirm the configuration assignments.
Furthermore, this method was extended to prepare multimodified hydrolysis-resistant AZTpSpCX2ppSA and AZTpSpCX2ppSAZT (X = H or F) as potential inhibitors of the AZT excision reaction by HIV-1 RT. The reactions were carried out by the coupling of adenosine or AZT H-phosphonate with trimetaphosphate analogs, taking advantage of the differential power of elemental sulfur to sulfurize H-phosphonate diesters but not monoesters. Enzymatic degradation was performed in order to assign configurations of the diastereomers and compare their enzymatic stabilities.
Note
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Ph.D.
Note
(type = bibliography)
Includes bibliographical references.
Subject
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Topic
Chemistry and Chemical Biology
Subject
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Topic
Dinucleoside polyphosphates
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
Identifier
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.16087
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ETD_417
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NjNbRU
Identifier
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doi:10.7282/T3PR7WDP
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ETD doctoral
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Rights
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The author owns the copyright to this work.
Copyright
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Copyright protected
Availability
Status
Open
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Name
Qianwei Han
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Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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Non-exclusive ETD license
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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