Boc-Lys(Z)-CH2Cl | 82869-11-2

• 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-Lys(Z)-CH2Cl
• 英文别名: benzyl N-[(5S)-7-chloro-5-[(2-methylpropan-2-yl)oxycarbonylamino]-6-oxoheptyl]carbamate
• CAS: 82869-11-2
• 化学式: C₂₀H₂₉ClN₂O₅
• 分子量: 412.914
• InChiKey: DDMOGGMDMSUHRS-INIZCTEOSA-N

物化性质

• 沸点：
  594.0±50.0 °C(Predicted)
• 密度：
  1.166±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  28
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Boc-Lys(Z)-CH2Cl 在 N-甲基吗啉 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 24.25h， 生成 benzyl N-[[4-[2-[[(3S)-1-chloro-2-oxo-7-(phenylmethoxycarbonylamino)heptan-3-yl]amino]-2-oxoethyl]phenyl]methyl]carbamate
  参考文献：
  名称：

  Exploring the Sn Binding Pockets in Gingipains by Newly Developed Inhibitors:  Structure-Based Design, Chemistry, and Activity

  摘要：

  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.

  DOI：

  10.1021/jm0600141
• 作为产物：
  描述：

  苄基叔丁基(7-重氮-6-氧代庚烷-1,5-二基)(S)-二氨基甲酸酯 在 盐酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 Boc-Lys(Z)-CH2Cl
  参考文献：
  名称：

  Exploring the Sn Binding Pockets in Gingipains by Newly Developed Inhibitors:  Structure-Based Design, Chemistry, and Activity

  摘要：

  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.

  DOI：

  10.1021/jm0600141

文献信息

• Synthesis of tripeptide chloromethyl ketones and examination of their inhibitory effects on plasmin and plasma kallikrein.
  作者：Yuko TSUDA、Naoki TENO、Yoshio OKADA、Keiko WANAKA、Miyako BOHGAKI、Akiko HIJIKATA-OKUNOMIYA、Utako OKAMOTO、Taketoshi NAITO、Shosuke OKAMOTO

  DOI：10.1248/cpb.37.3108

  日期：——

  With the aim of obtaining selective synthetic inhibitors of plasmin and plasma kallikrein, D-Ile-Phe-Lys-CH2Cl, Ile-Phe-Lys-CH2Cl, D-Ile-Phe-Arg-CH2Cl and Ile-Phe-Arg-CH2Cl were synthesized and their inhibitory activity against plasmin, plasma kallikrein and other trypsin-like serine proteinases was examined. Among them, D-Ile-Phe-Arg-CH2Cl exhibited a highly selective inhibitory activity against plasma kallikrein, yet D-Ile-Phe-Lys-CH2Cl exhibited nearly the same order of inhibitory activity against plasmin as well as plasma kallikren.

  为了获得针对纤溶酶和血浆激肽释放酶的选择性合成抑制剂，合成了D-Ile-Phe-Lys-CH2Cl、Ile-Phe-Lys-CH2Cl、D-Ile-Phe-Arg-CH2Cl和Ile-Phe-Arg-CH2Cl，并检测了它们对纤溶酶、血浆激肽释放酶和其他类胰蛋白酶丝氨酸蛋白酶的抑制活性。其中，D-Ile-Phe-Arg-CH2Cl表现出对血浆激肽释放酶的高度选择性抑制活性，而D-Ile-Phe-Lys-CH2Cl对纤溶酶和血浆激肽释放酶的抑制活性几乎相同。
• Amino Acids and Peptides. LII. Design and Synthesis of Opioid Mimetics Containing a Pyrazinone Ring and Examination of Their Opioid Receptor Binding Activity.
  作者：Yoshio OKADA、Masaki TSUKATANI、Hiroaki TAGUCHI、Toshio YOKOI、Sharon D. BRYANT、Lawrence H. LAZARUS

  DOI：10.1248/cpb.46.1374

  日期：——

  An amino group was introduced to the 3 or 6 position of a pyrazinone ring by cyclization of dipeptidyl chloromethyl ketones. Boc-Tyr-OH was coupled with the amino funciton, followed by removal of the Boc group to give pyrazinone ring-containing tyrosine derivatives. Of the various tyrosine derivatives prepared, 5-methyl-6-β-phenethyl-3-tyrosylaminobutyl-2(1H)-pyrazinone exhibited strong binding to the μ-opioid receptor with a Ki value of 55.8 nM and to the δ-opioid receptor with a Ki value of 2165 nM and with a Kiμ/Kiδ value of 0.026.

  通过二肽基氯甲基酮的环化反应，将氨基引入吡嗪酮环的3位或6位。将Boc-酪氨酸与氨基进行偶联，随后去除Boc保护基，得到含吡嗪酮环的酪氨酸衍生物。在制备的各种酪氨酸衍生物中，5-甲基-6-β-苯乙基-3-酪氨酰氨基丁基-2(1H)-吡嗪酮表现出对μ-阿片受体的强结合作用，其Ki值为55.8 nM，对δ-阿片受体的Ki值为2165 nM，且Kiμ/Kiδ值为0.026。
• Development of Active Center-Directed Inhibitors against Plasmin.
  作者：Naoki TENO、Keiko WANAKA、Yoshio OKADA、Yuko TSUDA、Utako OKAMOTO、Akiko HIJIKATA-OKUNOMIYA、Taketoshi NAITO、Shosuke OKAMOTO

  DOI：10.1248/cpb.39.2340

  日期：——

  Active center-directed inhibitors of plasmin were designed based on the structure of specific substrates of plasmin and then synthesized. Their effects on plasmin were examined and the structure-inhibitory activity relationship was studied. Nα-trans-4-Aminomethylcyclohexanecarbonyllysine 4-benzoylanilide (Tra-Lys-BZA) inhibited plasmin activities toward S-2251 and fibrin with IC50 values of 15 and 6.1 μM, respectively and Nα-trans-4-aminomethylcyclohexanecarbonyllysine 4-benzylpiperidine amide (Tra-Lys-BPP) did not show any detectable inhibitory activity. Moreover, it was revealed that Tra-Lys-4-methoxycarbonylanilide inhibited plasma kallikrein more potently than plasmin.

  基于纤溶酶的特定底物结构设计了活性中心导向的纤溶酶抑制剂，并进行了合成。研究了它们对纤溶酶的效应以及结构-抑制活性的关系。Nα-反式-4-氨甲基环己烷羰基赖氨酸4-苯甲酰苯胺（Tra-Lys-BZA）对S-2251和纤维蛋白的IC50值分别为15和6.1μM，而Nα-反式-4-氨甲基环己烷羰基赖氨酸4-苄基哌啶酰胺（Tra-Lys-BPP）则没有显示出任何可检测的抑制活性。此外，研究发现Tra-Lys-4-甲氧羰基苯胺对血浆激肽释放酶的抑制作用比纤溶酶更强。
• Amino acids and peptides. LVI. Synthesis of pyrazinone ring-containing opioid mimetics and examination of their opioid receptor binding activity
  作者：Yoshio Okada、Atsuko Fukumizu、Motohiro Takahashi、Junpei Yamazaki、Toshio Yokoi、Yuko Tsuda、Sharon D Bryant、Lawrence H Lazarus

  DOI：10.1016/s0040-4020(99)00908-4

  日期：1999.12

  6-bis(4-aminobutyl)-5-methyl-2(1H)-pyrazinone (15). Using above pyrazinone derivatives, three opioid mimetics were prepared (III-V). Derivatives containing 3 and 6 demonstrated weak μ and δ-opioid receptor affinities ranging from 1.6 mM to 4.1 mM while the opioid mimetic containing derivative 15 displayed higher μ-opioid receptor binding affinity (Kiμ = 61 nM) and selectivity ().

  二肽基氯甲基酮的环化得到6-（4-氨基丁基）-3-羧乙基-5-甲基-2（1 H）-吡嗪酮（3），3-（4-氨基丁基）-6-羧乙基-5-甲基-2 （1 H）-吡嗪酮（6）和3,6-双（4-氨基丁基）-5-甲基-2（1 H）-吡嗪酮（15）。使用上述吡嗪酮衍生物，制备了三种阿片样物质模拟物（III-V）。含衍生物3和6证实弱μ和δ阿片样物质受体的亲和力范围从1.6mm至4.1mm的，而阿片样物质模拟物含有衍生物15显示更高的μ阿片受体结合亲和性（ķ我μ= 61 nM）和选择性（）。
• AGENTS FOR THE MOLECULAR IMAGING OF SERINE-PROTEASE IN HUMAN PATHOLOGIES
  申请人：Michel Jean-Baptiste

  公开号：US20130243691A1

  公开（公告）日：2013-09-19

  The present invention is directed to the use of an irreversible ligand of a serine protease selected from the group consisting of leukocyte elastase, thrombin, tissue plasminogen activator (t-PA) and plasmin for the molecular imaging of said serine protease and the diagnosis of pathophysiological conditions associated with said serine protease activity.

  本发明涉及使用不可逆配体，所述配体为从白细胞弹性蛋白酶、凝血酶、组织型纤维蛋白原激活物（t-PA）和纤溶酶中选择的丝氨酸蛋白酶的配体，用于分子成像所述丝氨酸蛋白酶和诊断与所述丝氨酸蛋白酶活性相关的病理生理条件。