4-methoxy-N-methyl-N-[2-tri(propan-2-yl)silylethynyl]benzenesulfonamide | 1007597-73-0

• 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: 4-methoxy-N-methyl-N-[2-tri(propan-2-yl)silylethynyl]benzenesulfonamide
• CAS: 1007597-73-0
• 化学式: C₁₉H₃₁NO₃SSi
• 分子量: 381.612
• InChiKey: DEOHSNNAQQIKGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.49
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  55
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-methoxy-N-methyl-N-[2-tri(propan-2-yl)silylethynyl]benzenesulfonamide 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 以75.1 %的产率得到
  参考文献：
  名称：

  10.1002/anie.202404195

  摘要：

  AbstractRemarkable progress has been made in the development of cysteine‐targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e. lysine, or K) have emerged in recent years. Besides a highly conserved catalytic lysine, almost all human protein kinases possess an equally conserved glutamate/aspartate (e.g. E/D) that forms a K–E/D salt bridge within the enzyme's active site. Electrophilic ynamides were previously used as effective peptide coupling reagents and to develop E/D‐targeting covalent protein inhibitors/probes. In the present study, we report the first ynamide‐based small‐molecule inhibitors capable of inducing intramolecular cross‐linking of various protein kinases, leading to subsequent irreversible inhibition of kinase activity. Our strategy took advantage of the close distance between the highly conserved catalytic K and E/D residues in a targeted kinase, thus providing a conceptually general approach to achieve irreversible kinase inhibition with high specificity and desirable cellular potency. Finally, this ynamide‐facilitated, ligand‐induced mechanism leading to intramolecular kinase cross‐linking and inhibition was unequivocally established by using recombinant ABL kinase as a representative.

  DOI：

  10.1002/anie.202404195
• 作为产物：
  描述：

  对甲氧基苯磺酰氯 在 2-二甲氨基吡啶 、 potassium phosphate 、 1,10-菲罗啉 、 copper(II) sulfate 、 三乙胺 作用下， 以 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 9.0h， 生成 4-methoxy-N-methyl-N-[2-tri(propan-2-yl)silylethynyl]benzenesulfonamide
  参考文献：
  名称：

  10.1002/anie.202404195

  摘要：

  AbstractRemarkable progress has been made in the development of cysteine‐targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e. lysine, or K) have emerged in recent years. Besides a highly conserved catalytic lysine, almost all human protein kinases possess an equally conserved glutamate/aspartate (e.g. E/D) that forms a K–E/D salt bridge within the enzyme's active site. Electrophilic ynamides were previously used as effective peptide coupling reagents and to develop E/D‐targeting covalent protein inhibitors/probes. In the present study, we report the first ynamide‐based small‐molecule inhibitors capable of inducing intramolecular cross‐linking of various protein kinases, leading to subsequent irreversible inhibition of kinase activity. Our strategy took advantage of the close distance between the highly conserved catalytic K and E/D residues in a targeted kinase, thus providing a conceptually general approach to achieve irreversible kinase inhibition with high specificity and desirable cellular potency. Finally, this ynamide‐facilitated, ligand‐induced mechanism leading to intramolecular kinase cross‐linking and inhibition was unequivocally established by using recombinant ABL kinase as a representative.

  DOI：

  10.1002/anie.202404195

文献信息

• Copper-Catalyzed Aerobic Oxidative Amidation of Terminal Alkynes:  Efficient Synthesis of Ynamides
  作者：Tetsuya Hamada、Xuan Ye、Shannon S. Stahl

  DOI：10.1021/ja077406x

  日期：2008.1.1

  A copper-catalyzed method for the preparation of ynamides has been identified that proceeds via aerobic oxidative coupling of terminal alkynes with various nitrogen nucleophiles, including cyclic carbamates, amides and ureas, and N-alkyl-arylsulfonamides and indoles.

  已经确定了一种用于制备炔酰胺的铜催化方法，该方法通过末端炔烃与各种含氮亲核试剂（包括环状氨基甲酸酯、酰胺和脲以及 N-烷基-芳基磺酰胺和吲哚）的有氧氧化偶联进行。
• 10.1002/anie.202404195
  作者：Wang, Xuan、Sun, Jie、Huang, Huisi、Tang, Guanghui、Chen, Peng、Xiang, Menghua、Li, Lin、Zhang, Zhi-Min、Gao, Liqian、Yao, Shao Q.

  DOI：10.1002/anie.202404195

  日期：——

  AbstractRemarkable progress has been made in the development of cysteine‐targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e. lysine, or K) have emerged in recent years. Besides a highly conserved catalytic lysine, almost all human protein kinases possess an equally conserved glutamate/aspartate (e.g. E/D) that forms a K–E/D salt bridge within the enzyme's active site. Electrophilic ynamides were previously used as effective peptide coupling reagents and to develop E/D‐targeting covalent protein inhibitors/probes. In the present study, we report the first ynamide‐based small‐molecule inhibitors capable of inducing intramolecular cross‐linking of various protein kinases, leading to subsequent irreversible inhibition of kinase activity. Our strategy took advantage of the close distance between the highly conserved catalytic K and E/D residues in a targeted kinase, thus providing a conceptually general approach to achieve irreversible kinase inhibition with high specificity and desirable cellular potency. Finally, this ynamide‐facilitated, ligand‐induced mechanism leading to intramolecular kinase cross‐linking and inhibition was unequivocally established by using recombinant ABL kinase as a representative.