2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde | 1620897-88-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde
• 英文别名: 2-[(4-Chlorophenyl)methyl]-6-(2-oxochromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde；2-[(4-chlorophenyl)methyl]-6-(2-oxochromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde
• CAS: 1620897-88-2
• 化学式: C₂₁H₁₂ClN₃O₃S
• 分子量: 421.864
• InChiKey: IGQQLVMXFRSPTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-吲哚酮 、 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 在 哌啶 作用下， 以 甲醇 为溶剂， 以83%的产率得到3-((2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]-thiadiazol-5-yl) methylidene)-1,3-dihydro-2H-indol-2-one
  参考文献：
  名称：

  Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain

  摘要：

  The antiapoptotic protein BCL2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL2 inhibitor. Disarib showed selective cytotoxicity in BCL2 high cancer cell lines, and CLL patient primary cells, as compared to BCL2 low cell lines. BCL2 knockdown in cells rendered remarkable resistance to Disarib, while sensitivity was regained upon its ectopic expression, establishing target specificity. In silico, biochemical and biophysical studies demonstrated strong affinity of Disarib to BCL2, but not to other antiapoptotic BCL2 family members viz., BCL‐xL, BCL2A1 etc. Interestingly, biophysical studies showed that BH1 domain deletion mutant demonstrated ~ 67‐fold reduction in BCL2‐Disarib interaction, while it was only ~ 20‐fold in the case of BH3 deletion mutant, suggesting predominant involvement of the BH1 domain for Disarib binding. Thus, we report identification of a novel BCL2 inhibitor with a unique mechanism of BCL2 inhibition, as opposed to the well‐studied BH3 domain targeting.

  DOI：

  10.1111/febs.13815
• 作为产物：
  描述：

  2-氨基-5-(4-氯苄基)-1,3,4-噻二唑 在 三氯氧磷 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde
  参考文献：
  名称：

  2-(4-Chlorobenzyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazoles: Synthesis, cytotoxic activity and mechanism of action

  摘要：

  The cytotoxic activity of a new series of 2-(4'-chlorobenzyl)-5,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles against different human and murine cancer cell lines is reported. Among the tested compounds, two derivatives namely 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4i and 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate 5i emerged as the most potent against all the cell lines. To investigate the mechanism of action, we selected compounds 4i for cell cycle study, analysis of mitochondrial membrane potential and Annexin V-FITC flow cytometric analysis and DNA fragmentation assay. Results showed that 4i induced cytotoxicity by inducing apoptosis without arresting the cell cycle.

  DOI：

  10.1016/j.ejmech.2014.07.054

文献信息

• Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain
  作者：Divyaanka Iyer、Supriya V. Vartak、Archita Mishra、Gunaseelan Goldsmith、Sujeet Kumar、Mrinal Srivastava、Mahesh Hegde、Vidya Gopalakrishnan、Mark Glenn、Mahesh Velusamy、Bibha Choudhary、Nagesh Kalakonda、Subhas S. Karki、Avadhesha Surolia、Sathees C. Raghavan

  DOI：10.1111/febs.13815

  日期：2016.9

  The antiapoptotic protein BCL2 is overexpressed in several cancers and contributes to prolonged cell survival and chemoresistance, lending itself as an excellent target for cancer therapy. Here, we report the design, synthesis, and characterization of Disarib, a novel BCL2 inhibitor. Disarib showed selective cytotoxicity in BCL2 high cancer cell lines, and CLL patient primary cells, as compared to BCL2 low cell lines. BCL2 knockdown in cells rendered remarkable resistance to Disarib, while sensitivity was regained upon its ectopic expression, establishing target specificity. In silico, biochemical and biophysical studies demonstrated strong affinity of Disarib to BCL2, but not to other antiapoptotic BCL2 family members viz., BCL‐xL, BCL2A1 etc. Interestingly, biophysical studies showed that BH1 domain deletion mutant demonstrated ~ 67‐fold reduction in BCL2‐Disarib interaction, while it was only ~ 20‐fold in the case of BH3 deletion mutant, suggesting predominant involvement of the BH1 domain for Disarib binding. Thus, we report identification of a novel BCL2 inhibitor with a unique mechanism of BCL2 inhibition, as opposed to the well‐studied BH3 domain targeting.
• 2-(4-Chlorobenzyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazoles: Synthesis, cytotoxic activity and mechanism of action
  作者：Sujeet Kumar、Mahesh Hegde、Vidya Gopalakrishnan、Vinaya Kumar Renuka、Sureshbabu A. Ramareddy、Erik De Clercq、Dominique Schols、Anil Kumar Gudibabande Narasimhamurthy、Sathees C. Raghavan、Subhas S. Karki

  DOI：10.1016/j.ejmech.2014.07.054

  日期：2014.9

  The cytotoxic activity of a new series of 2-(4'-chlorobenzyl)-5,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles against different human and murine cancer cell lines is reported. Among the tested compounds, two derivatives namely 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4i and 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate 5i emerged as the most potent against all the cell lines. To investigate the mechanism of action, we selected compounds 4i for cell cycle study, analysis of mitochondrial membrane potential and Annexin V-FITC flow cytometric analysis and DNA fragmentation assay. Results showed that 4i induced cytotoxicity by inducing apoptosis without arresting the cell cycle.