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Novel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen

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TitleInfo (displayLabel = Citation Title); (type = uniform)
Title
Novel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen
Name (ID = NAME001); (type = personal)
NamePart (type = family)
Wu
NamePart (type = given)
Xinghua
DisplayForm
Xinghua Wu
Role
RoleTerm (authority = RULIB)
author
Name (ID = NAME002); (type = personal)
NamePart (type = family)
Hu
NamePart (type = given)
Longqin
Affiliation
Advisory Committee
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Longqin Hu
Role
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chair
Name (ID = NAME003); (type = personal)
NamePart (type = family)
LaVoie
NamePart (type = given)
Edmond
Affiliation
Advisory Committee
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Edmond J. LaVoie
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internal member
Name (ID = NAME004); (type = personal)
NamePart (type = family)
Rice
NamePart (type = given)
Joseph
Affiliation
Advisory Committee
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Joseph E. Rice
Role
RoleTerm (authority = RULIB)
internal member
Name (ID = NAME005); (type = personal)
NamePart (type = family)
Knapp
NamePart (type = given)
Spencer
Affiliation
Advisory Committee
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Spencer Knapp
Role
RoleTerm (authority = RULIB)
outside member
Name (ID = NAME006); (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (ID = NAME007); (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2008
DateOther (qualifier = exact); (type = degree)
2008-05
Language
LanguageTerm
English
PhysicalDescription
Form (authority = marcform)
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 ┬ÁM 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.
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references (p. 156-174).
Subject (ID = SUBJ1); (authority = RUETD)
Topic
Medicinal Chemistry
Subject (ID = SUBJ2); (authority = ETD-LCSH)
Topic
Prostate--Cancer
Subject (ID = SUBJ3); (authority = ETD-LCSH)
Topic
Prostate-specific antigen
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17057
Identifier
ETD_758
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3B27VND
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
AssociatedEntity (AUTHORITY = rulib); (ID = 1)
Name
Xinghua Wu
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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Type
Permission or license
Detail
Non-exclusive ETD license
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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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