2-methyl-4-(4-nitrophenyl)-5-oxo-N-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide | 695166-77-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-methyl-4-(4-nitrophenyl)-5-oxo-N-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide
• 英文别名: 2-methyl-4-(4-nitrophenyl)-5-oxo-N-phenyl-4,6,7,8-tetrahydro-1H-quinoline-3-carboxamide
• CAS: 695166-77-9
• 化学式: C₂₃H₂₁N₃O₄
• 分子量: 403.437
• InChiKey: ZRBOIOAOICNTPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  苯胺 在 ammonium acetate 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 、 乙醇 为溶剂， 反应 24.0h， 生成 2-methyl-4-(4-nitrophenyl)-5-oxo-N-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide
  参考文献：
  名称：

  Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

  摘要：

  Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.

  DOI：

  10.2147/dddt.s119995

文献信息

• Synthesis of 4,N-diaryl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides
  作者：V. L. Gein、M. I. Kazantseva、A. A. Kurbatova

  DOI：10.1134/s1070428011060091

  日期：2011.6

  Cyclohexane-1,3-dione reacted with substituted benzaldehydes and N-arylacetoacetamides in the presence of ammonium acetate under solvent-free conditions (150-160A degrees C, 10-20 min) to give the corresponding 4,N-diaryl-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamides. The product structure was determined by IR and (1)H NMR spectroscopy and mass spectrometry.
• Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study
  作者：Omolbanin Shahraki、Najmeh Edraki、Mehdi Khoshneviszadeh、Farshid Zargari、Sara Ranjbar、Luciano Saso、Omidreza Firuzi、Ramin Miri

  DOI：10.2147/dddt.s119995

  日期：——

  Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.