The Development of N-α-(2-Carboxyl)benzoyl-N5-(2-fluoro-1-iminoethyl)-l-ornithine Amide (o-F-amidine) and N-α-(2-Carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)-l-ornithine Amide (o-Cl-amidine) As Second Generation Protein Arginine Deiminase (PAD) Inhibitors
Citations Over TimeTop 10% of 2011 papers
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-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(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.
Related Papers
- → Amidine Functionality As a Conformational Probe of Cyclic Peptides(2020)19 cited
- → Synthesis of Bis(N-acylamidines) from Amidines and N-Acylbenzotriazoles(2010)2 cited
- → Addition reactions of primary and secondary aliphatic amines to the benzonitrile ligands in cis- and trans-[PtCl2(NCPh)2] complexes. X-ray structure of the amidine complex trans-[PtCl2{Z-N(H)C(NHBut)Ph}2](2002)44 cited
- → Superbasic Amidine Monodentate Ligands infac-[Re(CO)3(5,5′-Me2bipy)(Amidine)]BF4Complexes: Dependence of Amidine Configuration on the Remote Nitrogen Substituents(2010)19 cited
- → The Experimental Study on the continuous Anti-bacterial Potency of Coptidis rhizoma extract on Cultivation of Staphylococcus species(S. aureus, S. epidermidis)(2007)1 cited