cis-1-(4-bromo-phenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: cis-1-(4-bromo-phenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
• 英文别名: cis-1-(p-bromophenyl)-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline；methyl (1S,3S)-1-(4-bromophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
• 化学式: C₁₉H₁₇BrN₂O₂
• 分子量: 385.26
• InChiKey: UUKPOUWUKZFGJZ-IRXDYDNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  54.1
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  cis-1-(4-bromo-phenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester 在 碳酸氢钠 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 16.0h， 生成 (2S,8S)-2-(4-bromophenyl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione
  参考文献：
  名称：

  Exploring the PDE5 H-pocket by ensemble docking and structure-based design and synthesis of novel β-carboline derivatives

  摘要：

  By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-beta-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.09.029
• 作为产物：
  描述：

  D-色氨酸 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 101.08h， 生成 cis-1-(4-bromo-phenyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester
  参考文献：
  名称：

  扩展他达拉非支架的用途：开发新型选择性磷酸二酯酶 5 抑制剂和组蛋白脱乙酰酶抑制剂。

  摘要：

  在此，我们介绍了他达拉非类似物的新型化学系列的合成和表征，这些化学系列显示出不同的药理学特征。具有 6R、12aR 构型和由哌嗪二酮氮产生的侧链末端羧酸基团的化合物是有效的 PDE5 抑制剂，其中化合物 11 具有与他达拉非几乎相同的效力，并且比 PDE11（他达拉非最常见的脱靶）具有更高的选择性。将立体化学修饰为 6S、12aS 构型并采用异羟肟酸部分作为末端基团产生仅抑制 HDAC 的化合物。使用具有 6R、12aR 构型和异羟肟酸部分作为末端基团的化合物可以实现 PDE5/HDAC 双重抑制。针对不同来源的多种细胞系评估了合成化合物的抗癌活性。这些化合物对属于淋巴增殖性癌症以及实体瘤的细胞系具有抗癌活性。尽管之前的报道表明 PDE5 抑制剂具有抗癌活性，但这些化合物的生长抑制活性似乎仅依赖于 HDAC 抑制。化合物 26（泛 HDAC IC50 = 14 nM，PDE5 IC50 =

  DOI：

  10.1016/j.bioorg.2020.103742

文献信息

• Discovery and preliminary mechanism of 1-carbamoyl β-carbolines as new antifungal candidates
  作者：Tao Sheng、Mengmeng Kong、Yujie Wang、HuiJun Wu、Qin Gu、Anita Shyying Chuang、Shengkun Li、Xuewen Gao

  DOI：10.1016/j.ejmech.2021.113563

  日期：2021.10

  Natural β-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted β-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 μM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement

  天然β-咔啉生物碱是发现重要药物实体的理想模型。各种 1-取代的β-咔啉是由商业上廉价的色氨酸合成的，并在体外对禾谷菌具有显着的抗真菌活性。值得注意的是， 与 Silthiopham (EC 50  = 8.95 μM)相比，在 1 位具有甲酰胺的化合物4m (EC 50 = 0.45 μM) 显示出最佳功效和近 20 倍的抗真菌潜力增强。此外，化合物6，7和4I显示出优异的体外抗真菌活性以及针对B. cinerea和F. graminearum 的体内保护和治疗活性。初步机制研究表明，化合物4m导致活性氧积累、细胞膜破坏和组蛋白乙酰化失调。这些发现表明 1-氨基甲酰基β-咔啉可以作为发现新型广谱杀菌剂候选物的有前途的模型。
• Simple and efficient synthesis of tetrahydro-β-carbolines via the Pictet–Spengler reaction in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)
  作者：Li-Na Wang、Su-Li Shen、Jin Qu

  DOI：10.1039/c4ra03628j

  日期：——

  1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) can act as both the solvent and the catalyst to effectively promote the Pictet–Spengler reaction.

  1,1,1,3,3,3-六氟-2-丙醇（HFIP）可以作为溶剂和催化剂，有效地促进Pictet-Spengler反应。
• Water as an efficient medium for the synthesis of tetrahydro-β-carbolines via Pictet–Spengler reactions
  作者：Biswajit Saha、Sunil Sharma、Devesh Sawant、Bijoy Kundu

  DOI：10.1016/j.tetlet.2006.12.112

  日期：2007.2

  A mild and efficient protocol for the Pictet-Spengler reaction in water using an acid catalyst has been described. The condensation of tryptophan, tryptamine, and N-b-benzyl tryptophan with different aldehydes having both electron-withdrawing and -donating substituents in the presence of a catalytic amount of TFA in water furnished tetrahydro-beta-carbolines in good isolated yields. A salient feature of the water mediated Pictet-Spengler reaction was the general trend observed during the condensation of Trp-OMe and aryl/aliphatic aldehydes furnishing diastereomeric mixtures with a preference for the cis-isomer. (c) 2007 Elsevier Ltd. All rights reserved.
• Extending the use of tadalafil scaffold: Development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors
  作者：Ahmed K. ElHady、Shou-Ping Shih、Yu-Cheng Chen、Yi-Chang Liu、Nermin S. Ahmed、Adam B. Keeton、Gary A. Piazza、Matthias Engel、Ashraf H. Abadi、Mohammad Abdel-Halim

  DOI：10.1016/j.bioorg.2020.103742

  日期：2020.5

  Herein we present the synthesis and characterization of a novel chemical series of tadalafil analogues that display different pharmacological profiles. Compounds that have the 6R, 12aR configuration and terminal carboxylic acid group at the side chain arising from the piperazinedione nitrogen were potent PDE5 inhibitors, with compound 11 having almost equal potency to tadalafil and superior selectivity

  在此，我们介绍了他达拉非类似物的新型化学系列的合成和表征，这些化学系列显示出不同的药理学特征。具有 6R、12aR 构型和由哌嗪二酮氮产生的侧链末端羧酸基团的化合物是有效的 PDE5 抑制剂，其中化合物 11 具有与他达拉非几乎相同的效力，并且比 PDE11（他达拉非最常见的脱靶）具有更高的选择性。将立体化学修饰为 6S、12aS 构型并采用异羟肟酸部分作为末端基团产生仅抑制 HDAC 的化合物。使用具有 6R、12aR 构型和异羟肟酸部分作为末端基团的化合物可以实现 PDE5/HDAC 双重抑制。针对不同来源的多种细胞系评估了合成化合物的抗癌活性。这些化合物对属于淋巴增殖性癌症以及实体瘤的细胞系具有抗癌活性。尽管之前的报道表明 PDE5 抑制剂具有抗癌活性，但这些化合物的生长抑制活性似乎仅依赖于 HDAC 抑制。化合物 26（泛 HDAC IC50 = 14 nM，PDE5 IC50 =
• Exploring the PDE5 H-pocket by ensemble docking and structure-based design and synthesis of novel β-carboline derivatives
  作者：Nermin S. Ahmed、Amal H. Ali、Shreen M. El-Nashar、Bernard D. Gary、Alexandra M. Fajardo、Heather N. Tinsley、Gary A. Piazza、Matthias Negri、Ashraf H. Abadi

  DOI：10.1016/j.ejmech.2012.09.029

  日期：2012.11

  By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-beta-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking. (C) 2012 Elsevier Masson SAS. All rights reserved.