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Novel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen
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Wu, Xinghua. Novel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen. Retrieved from https://doi.org/doi:10.7282/T3B27VND

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Uniform TitleNovel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen
NameWu, Xinghua (author); Hu, Longqin (chair); LaVoie, Edmond (internal member); Rice, Joseph (internal member); Knapp, Spencer (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2008
Other Date2008-05 (degree)
SubjectMedicinal Chemistry, Prostate--Cancer, Prostate-specific antigen
Extentxv, 175 pages
DescriptionA 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.
NotePh.D.
NoteIncludes bibliographical references (p. 156-174).
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3B27VND
LanguageEnglish
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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