Synucleozid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: Synucleozid
• 英文别名: 2-[4-(4-carbamimidoylanilino)phenyl]-1H-indole-6-carboximidamide
• 化学式: C₂₂H₂₀N₆
• 分子量: 368.4
• InChiKey: TZRXNWCLKYWDNH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  128
• 氢给体数：
  6
• 氢受体数：
  3

文献信息

• TREATMENT OF C9FTD/ALS BY TARGETING RNA EXPANDED REPEAT SEQUENCES
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：US20170292129A1

  公开（公告）日：2017-10-12

  A repeat expansion in C90RF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC) exp ) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation producing “c9RAN proteins”. Since neutralizing r(GGGGCC) exp could inhibit these potentially toxic events, we sought to identify small molecule binders of r(GGGGCC)exp, Chemical and enzymatic probing of r(GGGGCC) 8 indicate it adopts a hairpin structure in equilibrium with a quadruplex structure, Using this model, bioactive small molecules targeting r(GGGGCC) exp were designed arid found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC) 66 and neurons trans-differentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC) exp -binding small molecules as a possible C9FTD/ALS therapeutic, and suggest c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC) exp .

  C90RF72基因中的重复扩展导致额颞叶痴呆和肌萎缩侧索硬化（c9FTD/ALS）。扩展重复的RNA（r（GGGGCC）exp）形成核聚焦或经历重复相关的非ATG（RAN）翻译，产生“c9RAN蛋白质”。由于中和r（GGGGCC）exp可以抑制这些潜在的有害事件，因此我们试图鉴定r（GGGGCC）exp的小分子结合物。对r（GGGGCC）8的化学和酶探测表明它在平衡状态下采用了一个发夹结构和四链结构。利用这个模型，设计了针对r（GGGGCC）exp的生物活性小分子，并发现它们在表达r（GGGGCC）66的培养细胞和由重复扩展携带者的成纤维细胞转分化而来的神经元中，显著抑制了RAN翻译和聚焦形成。最后，我们展示了c9ALS患者脑脊液中特异性检测到poly（GP）c9RAN蛋白。我们的发现强调了r（GGGGCC）exp结合小分子作为可能的C9FTD/ALS治疗方法，并暗示c9RAN蛋白可能作为药效学生物标志物，评估针对r（GGGGCC）exp的治疗的疗效。
• Treatment of C9FTD/ALS by targeting RNA expanded repeat sequences
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：US10465196B2

  公开（公告）日：2019-11-05

  A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation producing “c9RAN proteins”. Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons trans-differentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic, and suggest c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.

  C9ORF72 的重复扩增会导致额颞叶痴呆症和肌萎缩侧索硬化症（c9FTD/ALS）。扩增重复序列（r(GGGGCC)exp）的 RNA 会形成核病灶或进行重复序列相关的非ATG（RAN）翻译，产生 "c9RAN 蛋白"。由于中和 r(GGGGCC)exp 可以抑制这些潜在的毒性事件，我们试图找出 r(GGGGCC)exp 的小分子结合剂。r(GGGGCC)8的化学和酶学探测结果表明，它采用了与四重结构平衡的发夹结构。利用这一模型，我们设计了靶向 r(GGGGCC)exp 的生物活性小分子，并发现它们能显著抑制表达 r(GGGGCC)66 的培养细胞和从重复扩增携带者的成纤维细胞转分化而来的神经元中的 RAN 翻译和病灶形成。最后，我们发现在 c9ALS 患者的脑脊液中能特异性地检测到 poly(GP) c9RAN 蛋白。我们的研究结果突显了r(GGGGCC)exp结合小分子是一种可能的c9FTD/ALS疗法，并表明c9RAN蛋白有可能成为一种药效学生物标记物，用于评估针对r(GGGGCC)exp的疗法的疗效。