N2-(2-aminoethyl)-N4-(3-methoxybenzyl)-N6-(prop-2-yn-1-yl)-1,3,5-triazine-2,4,6-triamine | 1422258-70-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三嗪类
• 英文名称: N2-(2-aminoethyl)-N4-(3-methoxybenzyl)-N6-(prop-2-yn-1-yl)-1,3,5-triazine-2,4,6-triamine
• CAS: 1422258-70-5
• 化学式: C₁₆H₂₁N₇O
• 分子量: 327.389
• InChiKey: VDIGTLQKIYMBJF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.91
• 重原子数：
  24.0
• 可旋转键数：
  9.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  110.01
• 氢给体数：
  4.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  2-氯-5-硝基苯甲酸 、 N2-(2-aminoethyl)-N4-(3-methoxybenzyl)-N6-(prop-2-yn-1-yl)-1,3,5-triazine-2,4,6-triamine 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 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以0.033 g的产率得到2-chloro-N-(2-((4-((3-methoxybenzyl)amino)-6-(prop-2-yn-1-ylamino)-1,3,5-triazin-2-yl)amino)ethyl)-5-nitrobenzamide
  参考文献：
  名称：

  1,3,5-Triazine as a Modular Scaffold for Covalent Inhibitors with Streamlined Target Identification

  摘要：

  Small-molecule inhibitors can accelerate the functional annotation and validate the therapeutic potential of proteins implicated in disease. Phenotypic screens provide an effective platform to identify such pharmacological agents but are often hindered by challenges associated with target identification. For many protein targets, these bottlenecks can be overcome by incorporating electrophiles into small molecules to covalently trap interactions in vivo and by employing bioorthogonal handles to enrich the protein targets directly from a complex proteome. Here we present the trifunctionalized 1,3,5-triazine as an ideal modular scaffold for generating libraries of irreversible inhibitors with diverse target specificities. A divergent synthetic scheme was developed to derivatize the triazine with an electrophile for covalent modification of target proteins, an alkyne as a click-chemistry handle for target identification, and a diversity element to direct the compounds toward distinct subsets of the proteome. We specifically targeted our initial library toward cysteine-mediated protein activities through incorporation of thiol-specific electrophiles. From this initial screen we identified two compounds, RB-2-cb and RB-11-ca, which are cell permeable and highly selective covalent modifiers for Cys239 of beta-tubulin (TUBB) and Cys53 of protein disulfide isomerase (PDI) respectively. These compounds demonstrate in vitro and cellular potencies that are comparable to currently available modulators of tubulin polymerization and PDI activity. Our studies demonstrate the versatility of the triazine as a modular scaffold to generate potent and selective covalent modifiers of diverse protein families for chemical genetics applications.

  DOI：

  10.1021/ja400427e
• 作为产物：
  描述：

  4,6-dichloro-N-(prop-2-yn-1-yl)-1,3,5-triazin-2-amine 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 N2-(2-aminoethyl)-N4-(3-methoxybenzyl)-N6-(prop-2-yn-1-yl)-1,3,5-triazine-2,4,6-triamine
  参考文献：
  名称：

  1,3,5-Triazine as a Modular Scaffold for Covalent Inhibitors with Streamlined Target Identification

  摘要：

  Small-molecule inhibitors can accelerate the functional annotation and validate the therapeutic potential of proteins implicated in disease. Phenotypic screens provide an effective platform to identify such pharmacological agents but are often hindered by challenges associated with target identification. For many protein targets, these bottlenecks can be overcome by incorporating electrophiles into small molecules to covalently trap interactions in vivo and by employing bioorthogonal handles to enrich the protein targets directly from a complex proteome. Here we present the trifunctionalized 1,3,5-triazine as an ideal modular scaffold for generating libraries of irreversible inhibitors with diverse target specificities. A divergent synthetic scheme was developed to derivatize the triazine with an electrophile for covalent modification of target proteins, an alkyne as a click-chemistry handle for target identification, and a diversity element to direct the compounds toward distinct subsets of the proteome. We specifically targeted our initial library toward cysteine-mediated protein activities through incorporation of thiol-specific electrophiles. From this initial screen we identified two compounds, RB-2-cb and RB-11-ca, which are cell permeable and highly selective covalent modifiers for Cys239 of beta-tubulin (TUBB) and Cys53 of protein disulfide isomerase (PDI) respectively. These compounds demonstrate in vitro and cellular potencies that are comparable to currently available modulators of tubulin polymerization and PDI activity. Our studies demonstrate the versatility of the triazine as a modular scaffold to generate potent and selective covalent modifiers of diverse protein families for chemical genetics applications.

  DOI：

  10.1021/ja400427e