The 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.contributor.author | Causey, Corey P. | |
dc.contributor.author | Jones, Justin E. | |
dc.contributor.author | Slack, Jessica L. | |
dc.contributor.author | Kamei, Daisuke | |
dc.contributor.author | Jones, Larry E. | |
dc.contributor.author | Subramanian, Venkataraman | |
dc.contributor.author | Knuckley, Bryan | |
dc.contributor.author | Ebrahimi, Pedram | |
dc.contributor.author | Chumanevich, Alexander A. | |
dc.contributor.author | Luo, Yuan | |
dc.contributor.author | Hashimoto, Hiroshi | |
dc.contributor.author | Sato, Mamoru | |
dc.contributor.author | Hofseth, Lorne J. | |
dc.contributor.author | Thompson, Paul R | |
dc.date | 2022-08-11T08:11:00.000 | |
dc.date.accessioned | 2022-08-23T17:28:14Z | |
dc.date.available | 2022-08-23T17:28:14Z | |
dc.date.issued | 2011-10-13 | |
dc.date.submitted | 2015-05-22 | |
dc.identifier.citation | J 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.issn | 0022-2623 (Linking) | |
dc.identifier.doi | 10.1021/jm2008985 | |
dc.identifier.uri | http://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.abstract | 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. | |
dc.language.iso | en_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.url | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196593/ | |
dc.subject | Amidines | |
dc.subject | Antineoplastic Agents | |
dc.subject | Apoptosis | |
dc.subject | Biological Availability | |
dc.subject | Cell Differentiation | |
dc.subject | Cell Line, Tumor | |
dc.subject | Cell Survival | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Doxorubicin | |
dc.subject | Drug Screening Assays, Antitumor | |
dc.subject | Drug Synergism | |
dc.subject | Humans | |
dc.subject | Hydrolases | |
dc.subject | Kinetics | |
dc.subject | Molecular Structure | |
dc.subject | Ornithine | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Biochemistry | |
dc.subject | Enzymes and Coenzymes | |
dc.subject | Medicinal-Pharmaceutical Chemistry | |
dc.subject | Therapeutics | |
dc.title | The 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.type | Journal Article | |
dc.source.journaltitle | Journal of medicinal chemistry | |
dc.source.volume | 54 | |
dc.source.issue | 19 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/thompson/44 | |
dc.identifier.contextkey | 7135713 | |
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.submissionpath | thompson/44 | |
dc.contributor.department | Department of Biochemistry and Molecular Pharmacology | |
dc.source.pages | 6919-35 |