benzyl 1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropylcarbamate | 1282624-42-3

• 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: benzyl 1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropylcarbamate
• 英文别名: benzyl N-[1-bis(4-methylsulfanylphenoxy)phosphoryl-2-methylpropyl]carbamate
• CAS: 1282624-42-3
• 化学式: C₂₆H₃₀NO₅PS₂
• 分子量: 531.634
• InChiKey: INSHPFGAKWKAOG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.69
• 重原子数：
  35.0
• 可旋转键数：
  11.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  73.86
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  benzyl 1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropylcarbamate 在 氢溴酸 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 44.0h， 生成 2-(3-(2-((S)-1-((S)-2-((R)-1-(bis(4-(methylthio)phenoxy)-phosphoryl)-2-methylpropylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethyl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)acetic acid
  参考文献：
  名称：

  Human Neutrophil Elastase Phosphonic Inhibitors with Improved Potency of Action

  摘要：

  Herein, we present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of alpha-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, was also demonstrated. We also describe the preparation of single peptide diastereomers. The most active and selective compound developed possessed a k(inact)/K-1 of 2353000 M-1 s(-1), which is the most potent irreversible peptidyl inhibitor of human neutrophil elastase reported to date. The peptidyl inhibitors were demonstrated to be stable in PBS buffer and human plasma, as were their complexes with HNE.

  DOI：

  10.1021/jm300599x
• 作为产物：
  描述：

  4-(甲硫基)苯酚 在 溶剂黄146 、 三氯化磷 作用下， 以 乙腈 为溶剂， 反应 8.0h， 生成 benzyl 1-(bis(4-(methylthio)phenoxy)phosphoryl)-2-methylpropylcarbamate
  参考文献：
  名称：

  Human Neutrophil Elastase Phosphonic Inhibitors with Improved Potency of Action

  摘要：

  Herein, we present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of alpha-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, was also demonstrated. We also describe the preparation of single peptide diastereomers. The most active and selective compound developed possessed a k(inact)/K-1 of 2353000 M-1 s(-1), which is the most potent irreversible peptidyl inhibitor of human neutrophil elastase reported to date. The peptidyl inhibitors were demonstrated to be stable in PBS buffer and human plasma, as were their complexes with HNE.

  DOI：

  10.1021/jm300599x

文献信息

• A BODIPY-Tagged Phosphono Peptide as Activity-Based Probe for Human Leukocyte Elastase
  作者：Anna-Christina Schulz-Fincke、Michael Blaut、Annett Braune、Michael Gütschow

  DOI：10.1021/acsmedchemlett.7b00533

  日期：2018.4.12

  of biomedical studies. The chemotype of peptidic phosphonates was employed for the design of a new activity-based probe for human leukocyte elastase. Its structure combines the phosphonate warhead with an adequate peptide portion and a BODIPY fluorophore with a clickable ethinylphenyl moiety at meso position. The probe 6 was assembled by copper-catalyzed alkyne–azide 1,3-dipolar cycloaddition. It was

  人白细胞弹性蛋白酶在多种炎性疾病中起关键作用，并且是生物医学研究的重要课题。肽膦酸酯的化学型用于设计新的基于活性的人白细胞弹性蛋白酶探针。其结构结合了膦酸酯弹头具有足够的肽部分和BODIPY荧光团与一个可点击的ethinylphenyl部分内消旋位置。探针6由铜催化的炔-叠氮化物1,3-偶极环加成组装而成。它被表征为一种活性的定点弹性蛋白酶抑制剂，具有88400 M –1 s –1的二级失活速率常数。适合度6通过凝胶内荧光分析证实了其作为人白细胞弹性蛋白酶的荧光探针。针对一组相关蛋白酶的标记实验和抑制数据强调了探针对靶向白细胞弹性蛋白酶的选择性。
• Targeted Library of Phosphonic-Type Inhibitors of Human Neutrophil Elastase
  作者：Karolina Torzyk-Jurowska、Jaroslaw Ciekot、Lukasz Winiarski

  DOI：10.3390/molecules29051120

  日期：——

  the HNE inhibitor with kinact/KI value over 2,000,000 [M−1s−1]. In order to optimize its structure, over 100 novel tripeptidyl derivatives of α-aminoalkylphosphonate diaryl esters were synthesized, and their activity toward HNE was checked. To confirm the selectivity of the resultant compounds, several of the most active were additionally checked against the two other neutrophil proteases: proteinase

  尽管经过多年的研究，人类中性粒细胞弹性蛋白酶（HNE）仍然是许多研究人员感兴趣的领域。这种中性粒细胞丝氨酸蛋白酶的多功能代表是人体内发现的最具破坏性的酶之一，可以降解大部分细胞外基质。 HNE 的过度表达或失调可能导致多种炎症性疾病的发生。之前，我们提出了 kinact/KI 值超过 2,000,000 [M−1s−1] 的 HNE 抑制剂。为了优化其结构，合成了100多种新型α-氨基烷基膦酸二芳基酯三肽基衍生物，并检查了它们对HNE的活性。为了确认所得化合物的选择性，还针对另外两种中性粒细胞蛋白酶（蛋白酶 3 和组织蛋白酶 G）检查了几种最活跃的化合物。所开发的修饰使我们能够获得一种对人中性粒细胞弹性蛋白酶具有显着增强的抑制活性的化合物。对组织蛋白酶 G 具有选择性，但对蛋白酶 3 没有选择性。
• Simple phosphonic inhibitors of human neutrophil elastase
  作者：Marcin Sieńczyk、Łukasz Winiarski、Paulina Kasperkiewicz、Mateusz Psurski、Joanna Wietrzyk、Józef Oleksyszyn

  DOI：10.1016/j.bmcl.2011.01.083

  日期：2011.3

  Herein, we describe the synthesis and resulting activity of a complex series of alpha-aminophosphonate diaryl esters as irreversible human neutrophil elastase inhibitors and their selectivity preference for human neutrophil elastase over several other serine proteases such as porcine pancreatic elastase, trypsin, and chymotrypsin. We synthesized and examined the inhibitory potency of several new simple Cbz-protected alpha-aminoalkylphosphonate diaryl esters that yielded several new HNE inhibitors, where one of the obtained compounds Cbz-Val(P)(OC6H4-4-COOMe)(2) displayed an apparent second-order inhibition value at 33,015 M (1) s (1). (C) 2011 Elsevier Ltd. All rights reserved.
• Phosphonic pseudopeptides as human neutrophil elastase inhibitors—a combinatorial approach
  作者：Marcin Sieńczyk、Dawid Podgórski、Aleksandra Błażejewska、Julita Kulbacka、Jolanta Saczko、Józef Oleksyszyn

  DOI：10.1016/j.bmc.2010.12.008

  日期：2011.2

  Here we present a simple and rapid method for the construction of phosphonic peptide mimetic inhibitor libraries-products of Ugi and Passerini multicomponent condensations leading to the selection of new biologically active phosphonic pseudopeptides. As the starting isonitriles, 1-isocyanoalkylphosphonate diaryl ester derivatives were applied. The structure of the synthesized inhibitors was designed to target human neutrophil elastase, a serine protease whose uncontrolled activity may lead to development of several pathophysiological states such as rheumatoid arthritis, cystic fibrosis or tumor growth and invasion. After screening the inhibitory activity of our constructed libraries, the most active compounds were synthesized as single molecules. One of the obtained inhibitors, Cbz-Met-O-Met-Val(P)(OC6H4-p-Cl)(2), displayed apparent second-order inhibition value at 40,105 M-1 s(-1) as the diastereomers mixture. Inhibition potency and selectivity of action toward other serine proteases as well as the results of initial in vitro experiments regarding inhibitors influence on cancer cell proliferation are presented. (C) 2010 Elsevier Ltd. All rights reserved.