benzyl (S)-(6-acrylamido-1-((2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)amino)-1-oxohexan-2-yl)carbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: benzyl (S)-(6-acrylamido-1-((2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)amino)-1-oxohexan-2-yl)carbamate
• 英文别名: (S)-benzyl (6-acrylamido-1-((2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)amino)-1-oxohexan-2-yl)carbamate；benzyl N-[(2S)-1-[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]ethylamino]-1-oxo-6-(prop-2-enoylamino)hexan-2-yl]carbamate
• 化学式: C₃₁H₃₉N₅O₆S
• 分子量: 609.747
• InChiKey: ABYTXWHZRDCHFV-SANMLTNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  43
• 可旋转键数：
  17
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  154
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-alpha-Cbz-L-赖氨酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 反应 20.67h， 生成 benzyl (S)-(6-acrylamido-1-((2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)amino)-1-oxohexan-2-yl)carbamate
  参考文献：
  名称：

  Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase

  摘要：

  Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold. From this structure activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (k(inact)/K-I > 10(5) M-1 min(-1)). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 mu M, representing a significant improvement over our previously reported "hit" NC9.

  DOI：

  10.1021/acs.jmedchem.7b01070

文献信息

• Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
  作者：Abdullah Akbar、Nicole M. R. McNeil、Marie R. Albert、Viviane Ta、Gautam Adhikary、Karine Bourgeois、Richard L. Eckert、Jeffrey W. Keillor

  DOI：10.1021/acs.jmedchem.7b01070

  日期：2017.9.28

  Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold. From this structure activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (k(inact)/K-I > 10(5) M-1 min(-1)). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 mu M, representing a significant improvement over our previously reported "hit" NC9.