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dc.contributor.authorCausey, Corey P.
dc.contributor.authorJones, Justin E.
dc.contributor.authorSlack, Jessica L.
dc.contributor.authorKamei, Daisuke
dc.contributor.authorJones, Larry E.
dc.contributor.authorSubramanian, Venkataraman
dc.contributor.authorKnuckley, Bryan
dc.contributor.authorEbrahimi, Pedram
dc.contributor.authorChumanevich, Alexander A.
dc.contributor.authorLuo, Yuan
dc.contributor.authorHashimoto, Hiroshi
dc.contributor.authorSato, Mamoru
dc.contributor.authorHofseth, Lorne J.
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:14Z
dc.date.available2022-08-23T17:28:14Z
dc.date.issued2011-10-13
dc.date.submitted2015-05-22
dc.identifier.citationJ Med Chem. 2011 Oct 13;54(19):6919-35. doi: 10.1021/jm2008985. Epub 2011 Sep 16. <a href="http://dx.doi.org/10.1021/jm2008985">Link to article on publisher's site</a>
dc.identifier.issn0022-2623 (Linking)
dc.identifier.doi10.1021/jm2008985
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50035
dc.description<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>
dc.description.abstractProtein arginine deiminase (PAD) activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer. These enzymes, there are five in humans (PADs 1-4 and 6), regulate gene transcription, cellular differentiation, and the innate immune response. Building on our successful generation of F- and Cl-amidine, which irreversibly inhibit all of the PADs, a structure-activity relationship was performed to develop second generation compounds with improved potency and selectivity. Incorporation of a carboxylate ortho to the backbone amide resulted in the identification of N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine), as PAD inactivators with improved potency (up to 65-fold) and selectivity (up to 25-fold). Relative to F- and Cl-amidine, the compounds also show enhanced potency in cellulo. As such, these compounds will be versatile chemical probes of PAD function.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=21882827&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196593/
dc.subjectAmidines
dc.subjectAntineoplastic Agents
dc.subjectApoptosis
dc.subjectBiological Availability
dc.subjectCell Differentiation
dc.subjectCell Line, Tumor
dc.subjectCell Survival
dc.subjectCrystallography, X-Ray
dc.subjectDoxorubicin
dc.subjectDrug Screening Assays, Antitumor
dc.subjectDrug Synergism
dc.subjectHumans
dc.subjectHydrolases
dc.subjectKinetics
dc.subjectMolecular Structure
dc.subjectOrnithine
dc.subjectStructure-Activity Relationship
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleThe development of N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors
dc.typeJournal Article
dc.source.journaltitleJournal of medicinal chemistry
dc.source.volume54
dc.source.issue19
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/44
dc.identifier.contextkey7135713
html.description.abstract<p>Protein arginine deiminase (PAD) activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer. These enzymes, there are five in humans (PADs 1-4 and 6), regulate gene transcription, cellular differentiation, and the innate immune response. Building on our successful generation of F- and Cl-amidine, which irreversibly inhibit all of the PADs, a structure-activity relationship was performed to develop second generation compounds with improved potency and selectivity. Incorporation of a carboxylate ortho to the backbone amide resulted in the identification of N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine), as PAD inactivators with improved potency (up to 65-fold) and selectivity (up to 25-fold). Relative to F- and Cl-amidine, the compounds also show enhanced potency in cellulo. As such, these compounds will be versatile chemical probes of PAD function.</p>
dc.identifier.submissionpaththompson/44
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages6919-35


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