| 1589022-33-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• CAS: 1589022-33-2
• 化学式: C₂₃H₂₂N₆
• 分子量: 382.468
• InChiKey: SPRSXHODUUGEON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.48
• 重原子数：
  29.0
• 可旋转键数：
  0.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  82.08
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  tetra-tert-butylammonium hexafluorophosphate 、 tetra-tert-butylammonium tetrachloroaurate(III) 、 以 二氯甲烷 为溶剂， 反应 16.0h， 以23%的产率得到
  参考文献：
  名称：

  Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I

  摘要：

  Topoisomerase IB (Top 1) is a key eukaryotic nuclear enzyme that regulates the topology of DNA during replication and gene transcription. Anticancer drugs that block Top1 are either well-characterized interfacial poisons or lesser-known catalytic inhibitor compounds. Here we describe a new class of cytotoxic redox-stable cationic Au3+ macrocycles which, through hierarchical cluster analysis of cytotoxicity data for the lead compound, 3, were identified as either poisons or inhibitors of Top1. Two pivotal enzyme inhibition assays prove that the compounds are true catalytic inhibitors of Top1. Inhibition of human topoisomerase 11 alpha (Top2 alpha) by 3 was 2 orders of magnitude weaker than its inhibition of Top1, confirming that 3 is a type I-specific catalytic inhibitor. Importantly, Au3+ is essential for both DNA intercalation and enzyme inhibition. Macromolecular simulations show that 3 intercalates directly at the 5'-TA-3' dinucleotide sequence targeted by Top1 via crucial electrostatic interactions, which include pi-pi stacking and an Au center dot center dot center dot O contact involving a thymine carbonyl group, resolving the ambiguity of conventional (drug binds protein) vs unconventional (drug binds substrate) catalytic inhibition of the enzyme. Surface plasmon resonance studies confirm the molecular mechanism of action elucidated by the simulations.

  DOI：

  10.1021/ja412350f
• 作为产物：
  描述：

  1,2-二(1H-吡咯-2-基)-1,2-乙烷二酮 在 溶剂黄146 、 三乙胺 、 三氯氧磷 作用下， 以 甲醇 、 1,2-二氯乙烷 为溶剂， 反应 4.67h， 生成
  参考文献：
  名称：

  Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I

  摘要：

  Topoisomerase IB (Top 1) is a key eukaryotic nuclear enzyme that regulates the topology of DNA during replication and gene transcription. Anticancer drugs that block Top1 are either well-characterized interfacial poisons or lesser-known catalytic inhibitor compounds. Here we describe a new class of cytotoxic redox-stable cationic Au3+ macrocycles which, through hierarchical cluster analysis of cytotoxicity data for the lead compound, 3, were identified as either poisons or inhibitors of Top1. Two pivotal enzyme inhibition assays prove that the compounds are true catalytic inhibitors of Top1. Inhibition of human topoisomerase 11 alpha (Top2 alpha) by 3 was 2 orders of magnitude weaker than its inhibition of Top1, confirming that 3 is a type I-specific catalytic inhibitor. Importantly, Au3+ is essential for both DNA intercalation and enzyme inhibition. Macromolecular simulations show that 3 intercalates directly at the 5'-TA-3' dinucleotide sequence targeted by Top1 via crucial electrostatic interactions, which include pi-pi stacking and an Au center dot center dot center dot O contact involving a thymine carbonyl group, resolving the ambiguity of conventional (drug binds protein) vs unconventional (drug binds substrate) catalytic inhibition of the enzyme. Surface plasmon resonance studies confirm the molecular mechanism of action elucidated by the simulations.

  DOI：

  10.1021/ja412350f