(2,4-dichloro-5-fluorophenyl)(9H-pyrido[3,4-b]indol-1 yl)methanone

• 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: (2,4-dichloro-5-fluorophenyl)(9H-pyrido[3,4-b]indol-1 yl)methanone
• 英文别名: (2,4-dichloro-5-fluorophenyl)-(9H-pyrido[3,4-b]indol-1-yl)methanone
• 化学式: C₁₈H₉Cl₂FN₂O
• 分子量: 359.187
• InChiKey: WKWKOMOPKDWMKH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  45.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (2,4-dichloro-5-fluorophenyl)(9H-pyrido[3,4-b]indol-1 yl)methanone 以70%的产率得到4-chloro-5-fluoro fascaplysin
  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：

  2,4-二氯-5-氟苯乙酮 在 selenium(IV) oxide 、 palladium 10% on activated carbon 作用下， 以 1,4-二氧六环 、 水 、 溶剂黄146 为溶剂， 反应 7.0h， 生成 (2,4-dichloro-5-fluorophenyl)(9H-pyrido[3,4-b]indol-1 yl)methanone
  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

文献信息

• 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.