Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
J Med Chem. 2011 Oct 13;54(19):6919-35. doi: 10.1021/jm2008985. Epub 2011 Sep 16.
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.
蛋白质精氨酸脱亚氨酶（PAD）活性在许多人类疾病中上调，包括类风湿性关节炎、溃疡性结肠炎和癌症。这些酶，人类有五种（PADs 1-4 和 6），调节基因转录、细胞分化和先天免疫反应。在我们成功生成不可逆抑制所有 PAD 的 F-和 Cl-脒的基础上，进行了构效关系研究，以开发具有更高活性和选择性的第二代化合物。在骨干酰胺的邻位引入羧酸酯，导致鉴定出 N-α-(2-羧基)苯甲酰基-N(5)-(2-氟-1-亚氨基乙基)-l-鸟氨酸酰胺（o-F-脒）和 N-α-(2-羧基)苯甲酰基-N(5)-(2-氯-1-亚氨基乙基)-l-鸟氨酸酰胺（o-Cl-脒），作为具有提高的活性（高达 65 倍）和选择性（高达 25 倍）的 PAD 失活剂。与 F-和 Cl-脒相比，这些化合物在细胞内也表现出增强的活性。因此，这些化合物将成为 PAD 功能的多功能化学探针。
