Boc-Arg(Z)2-CH2Cl | 86807-94-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Boc-Arg(Z)2-CH2Cl
• 英文别名: benzyl N-[(4S)-6-chloro-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxohexyl]-N-[(Z)-N'-phenylmethoxycarbonylcarbamimidoyl]carbamate
• CAS: 86807-94-5
• 化学式: C₂₈H₃₅ClN₄O₇
• 分子量: 575.062
• InChiKey: MYNHQHOXWQXYGO-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  40
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  150
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Boc-Arg(Z)2-CH2Cl 在 N-甲基吗啉 、 盐酸 、 氯甲酸异丁酯 作用下， 以 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Tripeptidyl pyridinium methyl ketones as potent active site inhibitors of thrombin

  摘要：

  Several substituted methyl ketone derivatives of tripeptides with a C-terminal arginyl residue were synthesized as active site inhibitors of human alpha-thrombin. The most active compound among this series was the pyridinium methyl ketone D-Cha-Pro-Arg-PMK, which was characterized as a slow-binding inhibitor with a K-i of 0,19 nM. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0960-894x(96)00291-0
• 作为产物：
  描述：

  benzyl N-[(4S)-6-diazo-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxohexyl]-N-[(E)-N'-phenylmethoxycarbonylcarbamimidoyl]carbamate 在 盐酸 作用下， 以 四氢呋喃 为溶剂， 反应 0.17h， 生成 Boc-Arg(Z)2-CH2Cl
  参考文献：
  名称：

  Tripeptidyl pyridinium methyl ketones as potent active site inhibitors of thrombin

  摘要：

  Several substituted methyl ketone derivatives of tripeptides with a C-terminal arginyl residue were synthesized as active site inhibitors of human alpha-thrombin. The most active compound among this series was the pyridinium methyl ketone D-Cha-Pro-Arg-PMK, which was characterized as a slow-binding inhibitor with a K-i of 0,19 nM. Copyright (C) 1996 Elsevier Science Ltd

  DOI：

  10.1016/0960-894x(96)00291-0

文献信息

• Exploring the S<i>n</i> Binding Pockets in Gingipains by Newly Developed Inhibitors:  Structure-Based Design, Chemistry, and Activity
  作者：Arkadiusz Białas、Jolanta Grembecka、Daniel Krowarsch、Jacek Otlewski、Jan Potempa、Artur Mucha

  DOI：10.1021/jm0600141

  日期：2006.3.1

  Arg-gingipains (Rgps) and Lys-gingipain (Kgp) are cysteine proteinases secreted by Porphyromonas gingivalis, the major pathogen implicated in periodontal disease. Gingipains are essential to the bacterium for its virulence and survival, and development of inhibitors targeting these proteins provides an approach to treat periodontal diseases. Here, we present the first example of structure-based design of gingipains inhibitors, with the use of the crystal structure of RgpB and the homology model of Kgp. Chloromethyl ketones were selected as suitable compounds to explore the specificity of the Sn binding region of both enzymes. Three series of inhibitors bearing Arg or Lys at P1 and different substituents at P2 and P3 were designed, synthesized, and tested. High potency (k(obs)/[I] similar to 10(7) M-1 s(-1)) was achieved for small ligands, such as the dipeptide analogues. The detailed analysis of Sn binding pockets revealed the molecular basis of inhibitory affinity and provided insight into the structure-activity relationship.
• Potent Bivalent Thrombin Inhibitors:  Replacement of the Scissile Peptide Bond at P₁−P₁‘ with Arginyl Ketomethylene Isosteres
  作者：Torsten Steinmetzer、Bing Yan Zhu、Yasuo Konishi

  DOI：10.1021/jm9807297

  日期：1999.8.1

  We have designed highly potent synthetic bivalent thrombin inhibitors, which consist of an active site blocking segment, a fibrinogen recognition exosite blocking segment, and a linker connecting these segments. The bivalent inhibitors bind to the active site and the fibrinogen recognition exosite simultaneously. As a result, the inhibitors showed much higher affinity for thrombin than the individual blocking segments. Various arginyl ketomethylene isosteres Arg Psi-[CO-CH2-X]P-1' were incorporated into the bivalent inhibitors as P-1-P-1' segment to eliminate the scissile bond. The P-1' residue is a natural or unnatural amino acid; specifically, the incorporation of mercaptoacetic acid exhibited superiority in synthesis and affinity for thrombin. Inhibitor 16, (D-cyclohexylalanine)-Pro-Arg Psi[CO-CH2-S]Gly-(Gly)(4)-Asp-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Tyr-cyclohexylalanine-(D-Glu)-OH showed the lowest K-i value of 3.5 +/- 0.5 x 10(-13) M, which is comparable to that (K-i = 2.3 x 10(-13) M) of recombinant hirudin. Consequently we successfully reduced the size of the inhibitor from similar to 7 kDa of recombinant hirudin to similar to 2 kDa without losing the affinity.