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Novel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen
Descriptive
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Title
Novel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen
Name
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Wu
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Xinghua
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Xinghua Wu
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author
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Hu
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Longqin
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Advisory Committee
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Longqin Hu
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chair
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LaVoie
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Edmond
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Advisory Committee
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Edmond J. LaVoie
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internal member
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Rice
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Joseph
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Advisory Committee
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Joseph E. Rice
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internal member
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Knapp
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Spencer
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Advisory Committee
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Spencer Knapp
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outside member
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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theses
OriginInfo
DateCreated
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2008
DateOther
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2008-05
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
xv, 175 pages
Abstract
A series of nitroarylmethyl phosphoramide mustards was designed, synthesized and evaluated as nitroreductase-targeted prodrugs in gene-directed enzyme-prodrug therapy. Among them, fluorinated prodrugs showed improved bystander effect, cytotoxicity and selectivity. Based on the similar drug release mechanism via 1,6-elimination, a series of peptidylaminoarylmethyl phosphoramide mustards was designed, targeting prostate-specific antigen (PSA) as a prodrug-converting enzyme. By design, the prodrugs would only be activated after proteolytic cleavage of the PSA-specific peptide by PSA and then selectively release the highly cytotoxic phosphoramide mustard at the prostate tumor site. Among the synthesized prodrugs, the 2-fluorinated derivative had over 19-fold selectivity against PSA-secreting cancer cells with an IC50 of 5.3 µM according to in vitro antiproliferative cell assays.
To overcome the difficulty of synthesizing the designed peptidylaminoarylmethyl phosphoramide mustards, a novel selenocarboxylate/azide amidation methodology was developed. This strategy not only played a crucial role in the success of this project but also provided an excellent solution to the acylation of highly electron-deficient amines. Selenocarboxylate/azide amidation has been successfully used to synthesize a series of amino acid-pNAs and amino acid-AMCs that are important synthons in the synthesis of chromogenic and fluorogenic protease substrates.
To overcome the difficulty of synthesizing the designed peptidylaminoarylmethyl phosphoramide mustards, a novel selenocarboxylate/azide amidation methodology was developed. This strategy not only played a crucial role in the success of this project but also provided an excellent solution to the acylation of highly electron-deficient amines. Selenocarboxylate/azide amidation has been successfully used to synthesize a series of amino acid-pNAs and amino acid-AMCs that are important synthons in the synthesis of chromogenic and fluorogenic protease substrates.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references (p. 156-174).
Subject
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Topic
Medicinal Chemistry
Subject
(ID = SUBJ2);
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Topic
Prostate--Cancer
Subject
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Topic
Prostate-specific antigen
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Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17057
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ETD_758
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NjNbRU
Identifier
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doi:10.7282/T3B27VND
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ETD doctoral
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Rights
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The author owns the copyright to this work.
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Copyright protected
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Open
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Name
Xinghua Wu
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Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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Permission or license
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Non-exclusive ETD license
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Author Agreement License
Detail
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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