8-amino-8,11-oxapentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane

• 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: 8-amino-8,11-oxapentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane
• 英文别名: 5-oxahexacyclo[5.4.1.0^2,6.0^3,10.0^4,8.0^9,12]dodecan-4-amine；5-Oxahexacyclo[5.4.1.02,6.03,10.04,8.09,12]dodecan-4-amine
• 化学式: C₁₁H₁₃NO
• 分子量: 175.23
• InChiKey: FCSZSXVOOMAUCB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  35.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  8-amino-8,11-oxapentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane 在 thionyl chloride nitrate 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成
  参考文献：
  名称：

  S-Nitrosylation and Attenuation of Excessive Calcium Flux by Pentacycloundecane Derivatives

  摘要：

  一系列新型多环胺类化合物被合成，并测试其对钙通道和N-甲基-D-天冬氨酸受体的调节活性。这些合成化合物根据其氮氧化物供体部分分为两组：不饱和硝基化合物（1、2和3）和硝酸酯或硝酸盐（4、5和6）。硝酸盐通过羟基功能团与亚硫酰氯硝酸盐反应获得。所有合成的化合物均显示出显著的（p < 0.01）S-亚硝基化能力。采用氯化钾介导的荧光钙通量测定法评估多环胺的钙通道活性。所有化合物均表现出比先导结构NGP1-01更好的钙通道拮抗作用，化合物1在10 μM和1 μM浓度下显示出与市面上可获得的尼莫地平相当的钙通道阻断效果。化合物3和4在10 μM浓度下抑制钙通量至这些水平。使用荧光钙通量测定法在100 µM浓度下评估NMDA/甘氨酸介导的N-甲基-D-天冬氨酸受体（NMDAR）钙内流抑制作用。所有化合物均显示NMDAR拮抗作用，其中化合物1（25.4%）、2（20.24%）、3（33.14%）和6（24.55%）显示出最显著的NMDAR抑制活性（p < 0.01）。没有观察到化合物S-亚硝基化能力与其钙通道活性或NMDAR通道拮抗之间的明确相关性，这表明其他因素可能在五环十一烷胺通道调节机制中起更决定性的作用。这可能包括已描述的对五环十一烷胺通道活性有贡献的几何和立体体积考虑。所有合成的化合物均显示出有前景的钙通道和NMDAR通道抑制活性，并有望作为针对神经退行性疾病的潜在先导化合物用于药物开发。

  DOI：

  10.2174/1573406411208030361
• 作为产物：
  描述：

  五环[5.4.0.02,6.03,10.05,9]十一烷-8,11-二酮 在 sodium tetrahydroborate 、 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 为溶剂， 5.0~20.0 ℃ 、101.33 kPa 条件下， 反应 12.5h， 生成 8-amino-8,11-oxapentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane
  参考文献：
  名称：

  S-Nitrosylation and Attenuation of Excessive Calcium Flux by Pentacycloundecane Derivatives

  摘要：

  一系列新型多环胺类化合物被合成，并测试其对钙通道和N-甲基-D-天冬氨酸受体的调节活性。这些合成化合物根据其氮氧化物供体部分分为两组：不饱和硝基化合物（1、2和3）和硝酸酯或硝酸盐（4、5和6）。硝酸盐通过羟基功能团与亚硫酰氯硝酸盐反应获得。所有合成的化合物均显示出显著的（p < 0.01）S-亚硝基化能力。采用氯化钾介导的荧光钙通量测定法评估多环胺的钙通道活性。所有化合物均表现出比先导结构NGP1-01更好的钙通道拮抗作用，化合物1在10 μM和1 μM浓度下显示出与市面上可获得的尼莫地平相当的钙通道阻断效果。化合物3和4在10 μM浓度下抑制钙通量至这些水平。使用荧光钙通量测定法在100 µM浓度下评估NMDA/甘氨酸介导的N-甲基-D-天冬氨酸受体（NMDAR）钙内流抑制作用。所有化合物均显示NMDAR拮抗作用，其中化合物1（25.4%）、2（20.24%）、3（33.14%）和6（24.55%）显示出最显著的NMDAR抑制活性（p < 0.01）。没有观察到化合物S-亚硝基化能力与其钙通道活性或NMDAR通道拮抗之间的明确相关性，这表明其他因素可能在五环十一烷胺通道调节机制中起更决定性的作用。这可能包括已描述的对五环十一烷胺通道活性有贡献的几何和立体体积考虑。所有合成的化合物均显示出有前景的钙通道和NMDAR通道抑制活性，并有望作为针对神经退行性疾病的潜在先导化合物用于药物开发。

  DOI：

  10.2174/1573406411208030361

文献信息

• Synthesis and Biological Evaluations of NO-Donating Oxa- and Aza-Pentacycloundecane Derivatives as Potential Neuroprotective Candidates
  作者：Rajan Sharma、Jacques Joubert、Sarel Malan

  DOI：10.3390/molecules23020308

  日期：——

  In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds were done for cytotoxicity, neuroprotective abilities, the inhibition of N-methyl-d-aspartate (NMDA)-mediated Ca2+ influx, the inhibition of voltage-mediated Ca2+ influx, and S-nitrosylation abilities. All of the compounds showed low toxicity. With a few exceptions, most of the compounds displayed good neuroprotection and showed inhibitory activity for NMDA-mediated and voltage-gated calcium influx, ranging from high (>70%) to low (20–39%) inhibition. In the S-nitrosylation assay, the compounds with the nitro moiety as the NO-donating group exhibited low to good nitrosylation potency compared to the positive controls. From the biological evaluation of the tested compounds, it was not possible to obtain a simple correlation that could explain the results across all of the biological study domains. This can be ascribed to the independent processes evaluated in the different assays, which reiterate that neuroprotection is a result of multifactorial biochemical mechanisms and interactions. However, these results signify the important aspects of the pentacylcoundecylamine neuroprotectants across different biological study realms.

  为了利用多环笼状化合物的神经保护特性，并探究硝基苯基团的NO供体能力，合成了一系列化合物，其中不同的硝基苯基团被附加在氧和氮桥接的笼状衍生物上。对这些化合物进行了生物学评估，包括细胞毒性、神经保护能力、抑制N-甲基-D-天冬氨酸（NMDA）介导的Ca²⁺流入、抑制电压介导的Ca²⁺流入以及S-亚硝基化能力。所有化合物都显示出低毒性。除了少数例外，大多数化合物表现出良好的神经保护作用，并对NMDA介导和电压门控钙流入显示出抑制活性，抑制范围从高（>70%）到低（20-39%）。在S-亚硝基化试验中，带有硝基作为NO供体基团的化合物显示出与阳性对照相比从低到良好的亚硝基化效力。从对这些化合物的生物学评估中，无法获得一个简单的相关性来解释所有生物学研究领域的结果。这可以归因于在不同试验中评估的独立过程，这再次强调了神经保护是多因素生化机制和相互作用的结果。然而，这些结果表明了五环十一烷胺神经保护剂在不同生物学研究领域的重要方面。
• Design, synthesis and evaluation of pentacycloundecane and hexacycloundecane propargylamine derivatives as multifunctional neuroprotective agents
  作者：Frank T. Zindo、Sarel F. Malan、Sylvester I. Omoruyi、Adaze B. Enogieru、Okobi E. Ekpo、Jacques Joubert

  DOI：10.1016/j.ejmech.2018.11.051

  日期：2019.2

  The multifactorial pathophysiology of neurodegenerative disorders remains one of the main challenges in the design of a single molecule that may ultimately prevent the progression of these disorders in affected patients. In this article, we report on twelve novel polycyclic amine cage derivatives, synthesized with or without a propargylamine function, designed to possess inherent multifunctional neuroprotective activity. The mirr cytotoxicity assay results showed the SH-SY5Y human neuroblastoma cells to be viable with the twelve compounds, particularly at concentrations less than 10 mu M. The compounds also showed significant neuroprotective activity, ranging from 31% to 61% at 1 M, when assayed on SHSYSY human neuroblastoma cells in which neurodegeneration was induced by MPP+. Calcium regulation assays conducted on the same cell line showed the compounds to be significant VGCC blockers with activity ranging from 26.6% to 51.3% at 10 mu M; as well as significant NMDAr antagonists with compound 5 showing the best activity of 88.3% at 10 mu M. When assayed on human MAO isoenzymes, most of the compounds showed significant inhibitory activity, with compound 5 showing the best activity (MAO-B: IC50 = 1.70 mu M). Generally, the compounds were about 3-52 times more selective to the MAO-B isoenzyme than the MAO-A isoenzyme. Based on the time-dependency studies conducted, the compounds can be defined as reversible MAO inhibitors. Several structure activity relationships were derived from the various assays conducted, and the compounds' possible putative binding modes within the MAO-B enzyme cavity were assessed in silico. (C) 2018 Elsevier Masson SAS. All rights reserved.
• 2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: <i>In Vivo</i> Evaluation in a Murine Model of Acute Pancreatitis
  作者：Sandra Codony、Eugènia Pujol、Javier Pizarro、Ferran Feixas、Elena Valverde、M. Isabel Loza、José M. Brea、Elena Saez、Julen Oyarzabal、Antonio Pineda-Lucena、Belén Pérez、Concepción Pérez、María Isabel Rodríguez-Franco、Rosana Leiva、Sílvia Osuna、Christophe Morisseau、Bruce D. Hammock、Manuel Vázquez-Carrera、Santiago Vázquez

  DOI：10.1021/acs.jmedchem.0c00310

  日期：2020.9.10

  In vivo pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxaanalogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane 22, which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further in vitro and in vivo studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, 22 diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.
• GALIN F. Z.; LERMAN B. M.; TOLSTIKOV G. A., ZH. ORGAN. XIMII, 1979, 15 HO 4, 758-761
  作者：GALIN F. Z.、 LERMAN B. M.、 TOLSTIKOV G. A.

  DOI：——

  日期：——
• POLYCYCLIC COMPOUNDS FOR USE IN TREATING OCULAR NEURODEGENERATIVE DISEASES
  申请人：Van der Schyf Cornelis J.

  公开号：US20090143457A1

  公开（公告）日：2009-06-04

  Described herein are various compounds for treatment of ocular neurodegenerative diseases, including but not limited to glaucoma and diabetic retinopathy. The compounds described herein can act to attenuate and/or block calcium release from external neuronal environments as well as intracellular stores.