(R)-(+)-bornylamine

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (R)-(+)-bornylamine
• 英文别名: (2S,4R)-1,7,7-trimethylbicyclo[2.2.1]Heptan-2-amine
• 化学式: C₁₀H₁₉N
• 分子量: 153.268
• InChiKey: MDFWXZBEVCOVIO-HHCGNCNQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  26
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  3-氟-2-羟基苯甲醛 、 (R)-(+)-bornylamine 以 甲醇 为溶剂， 反应 1.0h， 以83%的产率得到3-fluoro-N-((1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)salicylimine
  参考文献：
  名称：

  Pd催化的脂族胺的立体和立体选择性sp3 CH芳基化：机理研究和合成应用

  摘要：

  3-溴-2-羟基苯甲醛已被用作伯胺在Pd催化的sp 3 -C-H芳基化中的高效瞬态导向基团（TDG）。这些实验结果已通过计算研究得到证实。提出的Pd / TDG催化方法还实现了进一步的功能化（串联氧化）和合成应用。

  DOI：

  10.1002/ejoc.202001428

文献信息

• Novel, thalidomide-like, non-cereblon binding drug tetrafluorobornylphthalimide mitigates inflammation and brain injury
  作者：Daniela Lecca、Shih-Chang Hsueh、Weiming Luo、David Tweedie、Dong Seok Kim、Abdul Mannan Baig、Neil Vargesson、Yu Kyung Kim、Inho Hwang、Sun Kim、Barry J. Hoffer、Yung-Hsiao Chiang、Nigel H. Greig

  DOI：10.1186/s12929-023-00907-5

  日期：——

  Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial anti-inflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs.

  TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti-inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions.

  TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 h post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice.

  TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity-associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurological disorders involving a neuroinflammatory component.

  摘要 研究背景 抑制小胶质细胞诱导的过度神经炎症是包括创伤性脑损伤（TBI）在内的各种神经系统疾病的一种潜在治疗策略，可通过沙利度胺类药物来实现，尽管这类已获批准的药物存在潜在的致畸性。四氟硼酰邻苯二甲酰亚胺（TFBP）和四氟硼酰邻苯二甲酰亚胺（TFNBP）的产生保留了沙利度胺类免疫调节亚胺药物（IMiD）的核心邻苯二甲酰亚胺结构。不过，经典的戊二酰亚胺环被桥接环结构所取代。因此，TFBP/TFNBP 在设计上保留了 IMiDs 的有益抗炎特性，但重要的是，它阻碍了脑龙的结合，而脑龙的结合正是沙利度胺类药物不良作用的根源。 研究方法 合成了 TFBP/TFNBP，并在人类和啮齿类动物细胞培养物中对其与脑龙的结合和抗炎作用进行了评估。在鸡胚胎中评估了致畸潜能，并在受到脂多糖（LPS）或受控皮质冲击（CCI）中度创伤性脑损伤（TBI）的啮齿动物体内评估了抗炎作用。为深入了解药物/脑龙的结合相互作用，还进行了分子建模。 研究结果 TFBP/TFNBP 可降低小鼠巨噬细胞样 RAW264.7 细胞培养物和受到 LPS 挑战的啮齿动物体内的炎症指标，从而降低促炎细胞因子。结合研究表明，它与脑龙的相互作用极小，不会导致与致畸相关的转录因子 SALL4 降解，也不会在鸡胚实验中产生致畸作用。为了评估 TFBP 抗炎作用的生物学相关性，在 CCI TBI 损伤后 1 小时和 24 小时给小鼠注射了两种剂量的 TFBP。与药物治疗相比，TFBP 可减少创伤性脑损伤病灶的大小，并可减少创伤性脑损伤引起的活化小胶质细胞表型。受伤后 1 周和 2 周的行为评估表明，与使用药物治疗的小鼠相比，TFBP 能更快地恢复 TBI 引起的运动协调和平衡障碍。 结论 TFBP 和 TFNBP 代表了一类新的沙利度胺类 IMiD，它们能降低促炎细胞因子的生成，但缺乏与脑隆的结合，而脑隆是致畸的主要相关机制。这使得 TFBP 和 TFNBP 在临床应用中可能比传统的 IMiD 更安全。TFBP 提供了一种缓解与中度创伤性脑损伤相关的过度神经炎症的策略，从而改善行为结果，值得在涉及神经炎症成分的神经系统疾病中进一步研究。 图表摘要
• NPR-B agonists
  申请人：Shire Orphan Therapies GmbH

  公开号：US10196423B2

  公开（公告）日：2019-02-05

  Disclosed are novel compounds having NPR-B agonistic activity. Preferred compounds are linear peptides containing 8-13 conventional or non-conventional L- or D-amino acid residues connected to one another via peptide bonds.

  所公开的是具有 NPR-B 激动活性的新型化合物。优选化合物是线性肽，含有 8-13 个通过肽键相互连接的常规或非常规 L 或 D 氨基酸残基。
• NOVEL NPR-B AGONISTS
  申请人：Osterkamp Frank

  公开号：US20110077381A1

  公开（公告）日：2011-03-31

  Disclosed are novel compounds having NPR-B agonistic activity. Preferred compounds are linear peptides containing 8-13 conventional or non-conventional L- or D-amino acid residues connected to one another via peptide bonds.
• Novel NPR-B Agonists
  申请人：SHIRE ORPHAN THERAPIES GMBH

  公开号：US20160194357A1

  公开（公告）日：2016-07-07

  Disclosed are novel compounds having NPR-B agonistic activity. Preferred compounds are linear peptides containing 8-13 conventional or non-conventional L- or D-amino acid residues connected to one another via peptide bonds.
• NPR-B Agonists
  申请人：Shire Orphan Therapies GmbH

  公开号：US20170313743A1

  公开（公告）日：2017-11-02

  Disclosed are novel compounds having NPR-B agonistic activity. Preferred compounds are linear peptides containing 8-13 conventional or non-conventional L- or D-amino acid residues connected to one another via peptide bonds.