(9H-pyrido[3,4-b]indol-1-yl)(4-(trifluoromethyl)phenyl)methanone | 1148028-86-7

• 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: (9H-pyrido[3,4-b]indol-1-yl)(4-(trifluoromethyl)phenyl)methanone
• 英文别名: (4-trifluoromethylphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone；9H-pyrido[3,4-b]indol-1-yl-[4-(trifluoromethyl)phenyl]methanone
• CAS: 1148028-86-7
• 化学式: C₁₉H₁₁F₃N₂O
• 分子量: 340.304
• InChiKey: FHKLTXMZKQMWDB-UHFFFAOYSA-N

物化性质

• 熔点：
  190.3-192 °C
• 沸点：
  525.8±50.0 °C(predicted)
• 密度：
  1.412±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  45.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (9H-pyrido[3,4-b]indol-1-yl)(4-(trifluoromethyl)phenyl)methanone 、 碘甲烷 以 乙腈 为溶剂， 反应 12.0h， 以75%的产率得到1-(4-trifluoromethylbenzoyl)-2-methyl-beta-carbolinium iodide
  参考文献：
  名称：

  Discovery of a marine-derived bis-indole alkaloid fascaplysin, as a new class of potent P-glycoprotein inducer and establishment of its structure–activity relationship

  摘要：

  The screening of IIIM natural products repository for P-gp modulatory activity in P-gp over-expressing human adenocarcinoma LS-180 cells led to the identification of 7 natural products viz. withaferin, podophyllotoxin, 3-demethylcolchicine, agnuside, reserpine, seseberecine and fascaplysin as P-gp inducers. Fascaplysin (6a), a marine-derived bis-indole alkaloid, was the most potent among all of them, showing induction of P-gp with EC50 value of 25 nM. P-gp induction is one of the recently targeted strategy to increase amyloid-beta clearance from Alzheimer brains. Thus, we pursued a medicinal chemistry of fascaplysin to establish its structure activity relationship for P-gp induction activity. Four series of analogs viz, substituted quaternary fascaplysin analogs, D-ring opened quaternary analogs, D-ring opened non-quaternary analogs, and beta-carbolinium analogs were synthesized and screened for P-gp induction activity. Among the total of 48 analogs screened, only quaternary nitrogen containing analogs 6a-g and 10a, 10h-1 displayed promising P-gp induction activity; whereas non-planar non-quaternary analogs 9a-m, 13a-n, 15a-h were devoid of this activity. The P-gp induction activity of best compounds was then confirmed by western-blot analysis, which indicated that fascaplysin (6a) along with 4,5-difluoro analog of fascaplysin 6f and D-ring opened analog 10j displayed 4-8 fold increase in P-gp expression in LS-180 cells at 1 mu M. Additionally, compounds 6a and 6f also showed inhibition of acetylcholinestease (AChE), an enzyme responsible for neuronal loss in Alzheimer's disease. Thus, fascaplysin and its analogs showing promising P-gp induction along with AChE inhibition at 1 mu M, with good safety window (LS-180: IC50 > 10 mu M, hGF: 4 mu M), clearly indicates their promise for development as an anti-Alzheimer agent. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.049
• 作为产物：
  描述：

  4-三氟甲基苯甲酰甲醛 、 DL-色氨酸 在 montmorillonite K-10 、 palladium 10% on activated carbon 作用下， 以 二氯甲烷 、 甲醇 为溶剂， 反应 0.25h， 以81%的产率得到(9H-pyrido[3,4-b]indol-1-yl)(4-(trifluoromethyl)phenyl)methanone
  参考文献：
  名称：

  A direct synthesis of β-carbolines via a three-step one-pot domino approach with a bifunctional Pd/C/K-10 catalyst

  摘要：

  A rapid, microwave-assisted synthesis of beta-carbolines via a Successive condensation/cyclization/dehydrogenation approach is described. This methodology involves the coupling of various tryptamines with aromatic aldehydes/glyoxals. The product imine undergoes a Pictet-Spengler cyclization followed by a final dehydrogenation to yield beta-carbolines in a three-step domino reaction. The use of the bifunctional catalyst Pd/C/K-10 combined with microwave irradiation enabled the synthesis of beta-carbolines in short reaction times and in good to excellent yields. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2009.01.143

文献信息

• Photoredox Generated Vinyl Radicals: Synthesis of Bisindoles and β-Carbolines
  作者：Neha Chalotra、Ajaz Ahmed、Masood Ahmad Rizvi、Zakir Hussain、Qazi Naveed Ahmed、Bhahwal Ali Shah

  DOI：10.1021/acs.joc.8b02193

  日期：2018.12.7

  A photoredox catalyzed approach enabling use of alkynes as surrogate of 2-oxoaldehydes/1,2-diones is reported. The method overcomes the difficulty associated with application of unsubstituted aliphatic α-oxoaldehydes, which has hitherto limited their general use. Indoles, tryptamine, and tryptophan methyl ester participated in the reaction to give a variety of α-oxo based analogues. Quantum yield investigations

  据报道，光氧化还原催化的方法能够使用炔烃作为2-氧醛/ 1,2-二酮的替代物。该方法克服了与未取代的脂族α-氧醛的施用相关的困难，该困难迄今限制了它们的一般用途。吲哚，色胺和色氨酸甲酯参与了反应，得到了多种基于α-氧代的类似物。量子产率研究支持自由基链机制。
• Synthesis and application of β-carbolines as novel multi-functional anti-Alzheimer’s disease agents
  作者：William Horton、Abha Sood、Swarada Peerannawar、Nandor Kugyela、Aditya Kulkarni、Rekha Tulsan、Chris D. Tran、Jessica Soule、Harry LeVine、Béla Török、Marianna Török

  DOI：10.1016/j.bmcl.2016.11.067

  日期：2017.1

  The design, synthesis and assessment of β-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer’s disease (AD) pathology, are described. The activity of the compounds was determined in Aβ self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant

  描述，设计和合成的基于β-咔啉核的化合物作为潜在的多功能药物，可以对抗几种可能在阿尔茨海默氏病（AD）病理中起重要作用的过程。通过Aβ自组装（原纤维和低聚物形成）和胆碱酯酶（AChE，BuChE）的活性抑制来确定化合物的活性，并评估其抗氧化性能。为了深入了解化合物的作用方式，对抑制剂-Aβ复合物的形成进行了HR-MS研究，并对抑制剂-BuChE相互作用进行了分子对接。尽管几种化合物在单独的测定中显示出强大的活性，但化合物14作为有前途的多靶标前导物出现，用于进一步的结构-活性关系研究。
• A direct synthesis of β-carbolines via a three-step one-pot domino approach with a bifunctional Pd/C/K-10 catalyst
  作者：Aditya Kulkarni、Mohammed Abid、Béla Török、Xudong Huang

  DOI：10.1016/j.tetlet.2009.01.143

  日期：2009.4

  A rapid, microwave-assisted synthesis of beta-carbolines via a Successive condensation/cyclization/dehydrogenation approach is described. This methodology involves the coupling of various tryptamines with aromatic aldehydes/glyoxals. The product imine undergoes a Pictet-Spengler cyclization followed by a final dehydrogenation to yield beta-carbolines in a three-step domino reaction. The use of the bifunctional catalyst Pd/C/K-10 combined with microwave irradiation enabled the synthesis of beta-carbolines in short reaction times and in good to excellent yields. (C) 2009 Elsevier Ltd. All rights reserved.
• Discovery of a marine-derived bis-indole alkaloid fascaplysin, as a new class of potent P-glycoprotein inducer and establishment of its structure–activity relationship
  作者：Sudhakar Manda、Sadhana Sharma、Abubakar Wani、Prashant Joshi、Vikas Kumar、Santosh K. Guru、Sonali S. Bharate、Shashi Bhushan、Ram A. Vishwakarma、Ajay Kumar、Sandip B. Bharate

  DOI：10.1016/j.ejmech.2015.10.049

  日期：2016.1

  The screening of IIIM natural products repository for P-gp modulatory activity in P-gp over-expressing human adenocarcinoma LS-180 cells led to the identification of 7 natural products viz. withaferin, podophyllotoxin, 3-demethylcolchicine, agnuside, reserpine, seseberecine and fascaplysin as P-gp inducers. Fascaplysin (6a), a marine-derived bis-indole alkaloid, was the most potent among all of them, showing induction of P-gp with EC50 value of 25 nM. P-gp induction is one of the recently targeted strategy to increase amyloid-beta clearance from Alzheimer brains. Thus, we pursued a medicinal chemistry of fascaplysin to establish its structure activity relationship for P-gp induction activity. Four series of analogs viz, substituted quaternary fascaplysin analogs, D-ring opened quaternary analogs, D-ring opened non-quaternary analogs, and beta-carbolinium analogs were synthesized and screened for P-gp induction activity. Among the total of 48 analogs screened, only quaternary nitrogen containing analogs 6a-g and 10a, 10h-1 displayed promising P-gp induction activity; whereas non-planar non-quaternary analogs 9a-m, 13a-n, 15a-h were devoid of this activity. The P-gp induction activity of best compounds was then confirmed by western-blot analysis, which indicated that fascaplysin (6a) along with 4,5-difluoro analog of fascaplysin 6f and D-ring opened analog 10j displayed 4-8 fold increase in P-gp expression in LS-180 cells at 1 mu M. Additionally, compounds 6a and 6f also showed inhibition of acetylcholinestease (AChE), an enzyme responsible for neuronal loss in Alzheimer's disease. Thus, fascaplysin and its analogs showing promising P-gp induction along with AChE inhibition at 1 mu M, with good safety window (LS-180: IC50 > 10 mu M, hGF: 4 mu M), clearly indicates their promise for development as an anti-Alzheimer agent. (C) 2015 Elsevier Masson SAS. All rights reserved.