Causey, Corey P.Jones, Justin E.Slack, Jessica L.Kamei, DaisukeJones, Larry E.Subramanian, VenkataramanKnuckley, BryanEbrahimi, PedramChumanevich, Alexander A.Luo, YuanHashimoto, HiroshiSato, MamoruHofseth, Lorne J.Thompson, Paul R2022-08-232022-08-232011-10-132015-05-22J 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>0022-2623 (Linking)10.1021/jm2008985https://hdl.handle.net/20.500.14038/50035<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</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.en-USAmidinesAntineoplastic AgentsApoptosisBiological AvailabilityCell DifferentiationCell Line, TumorCell SurvivalCrystallography, X-RayDoxorubicinDrug Screening Assays, AntitumorDrug SynergismHumansHydrolasesKineticsMolecular StructureOrnithineStructure-Activity RelationshipBiochemistryEnzymes and CoenzymesMedicinal-Pharmaceutical ChemistryTherapeuticsJournal Articlehttps://escholarship.umassmed.edu/thompson/447135713thompson/44