4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta [4,5] thieno[2,3-d] pyrimidine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta [4,5] thieno[2,3-d] pyrimidine
• 英文别名: 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine；12-piperazin-1-yl-7-thia-9,11-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene
• 化学式: C₁₃H₁₆N₄S
• 分子量: 260.363
• InChiKey: MFSBJNOISFKTFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  69.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  氯乙酸苯酯 、 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta [4,5] thieno[2,3-d] pyrimidine 在 碳酸氢钠 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以68%的产率得到phenyl-2-[4-(6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d] pyrimidin-4-yl)-piperazin-1-yl] acetate
  参考文献：
  名称：

  Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines

  摘要：

  Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs) this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANG-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 mu M. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-alpha) inhibitory activity, with IC50 value 0.155 mu M. Docking study was carried out into PDGFR-alpha active site which showed comparable binding mode to that of FDA approved PDGFR-alpha inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.

  DOI：

  10.1016/j.bioorg.2019.103472
• 作为产物：
  描述：

  2-氨基-5,6-二氢-4H-环戊烯并噻吩-3-甲腈 在 硫酸 、 三氯氧磷 作用下， 以 异丙醇 为溶剂， 反应 13.0h， 生成 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta [4,5] thieno[2,3-d] pyrimidine
  参考文献：
  名称：

  Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines

  摘要：

  Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs) this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANG-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 mu M. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-alpha) inhibitory activity, with IC50 value 0.155 mu M. Docking study was carried out into PDGFR-alpha active site which showed comparable binding mode to that of FDA approved PDGFR-alpha inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.

  DOI：

  10.1016/j.bioorg.2019.103472

文献信息

• Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells
  作者：Meng Yu、Minghui Zeng、Zhaoping Pan、Fengbo Wu、Li Guo、Gu He

  DOI：10.1016/j.ejmech.2020.112076

  日期：2020.3

  derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and potently inhibited the proliferation of HepG2, Hep3B, Huh-7 and SMMC-7721 cancer cell lines. Among these derivatives, the compound 9f demonstrated the best inhibitory activities on AKT1 (IC50 = 0.034 μM)

  在这项研究中，设计，合成和评估了一系列噻吩并[2,3-d]嘧啶衍生物，并将其作为新型AKT1抑制剂进行了评估。体外抗肿瘤测定结果表明，化合物9d-g和9i有效抑制AKT1的酶活性，并有效抑制HepG2，Hep3B，Huh-7和SMMC-7721癌细胞系的增殖。在这些衍生物中，化合物9f对AKT1（IC50 = 0.034μM）和Huh-7细胞（IC50 = 0.076μM）表现出最佳的抑制活性。一组生物学实验表明，化合物9f通过Akt / mTOR信号通路介导的自噬机制抑制了Huh-7的细胞增殖。此外，在皮下Huh-7异种移植模型中验证了9f的抗肿瘤能力。一起，
• Starch Nanoparticles for Enhancement of Oral Bioavailability of a Newly Synthesized Thienopyrimidine Derivative with Anti-Proliferative Activity Against Pancreatic Cancer
  作者：Ahmed R Gardouh、Ahmed SG Srag El-Din、Mohamed SH Salem、Yasser Moustafa、Shadeed Gad

  DOI：10.2147/dddt.s321962

  日期：——

  Purpose: This research aimed to improve water solubility and oral bioavailability of a newly synthesized thienopyrimidine derivative (TPD) with anti-pancreatic cancer activity by loading on starch nanoparticles (SNPs). Methods: TPD was synthesized, purified and its ADME behavior was predicted using Swiss ADME software. A UV spectroscopy method was developed and validated to measure TPD concentration at various dosage forms. SNPs loaded with TPD (SNPs-TPD) were prepared, characterized for particle size, polydispersity index, zeta potential, transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), entrapment efficiency, in-vitro release, and in-vivo animal study. Results: The Swiss ADME results showed that TPD can be administered orally; however, it has low oral bioavailability (0.55) and poor water solubility. The significant regression coefficient of the calibration curve (r2 = 0.9995), the precision (%RSD < 0.5%) and the accuracy (99.46-101.72%) confirmed the efficacy of the developed UV method. SNPs-TPD had a spherical monodispersed (PDI= 0.12) shape, nanoparticle size (22.98 ± 4.23) and good stability (-21 ± 4.72 mV). Moreover, FT-IR and DSC revealed changes in the physicochemical structure of starch resulting in SNPs formation. The entrapment efficiency was 97% ± 0.45%, and the in-vitro release showed that the SNPs enhanced the solubility of the TPD. The in-vivo animal study and histopathology showed that SNPs enhanced the oral bioavailability of TPD against solid Ehrlich carcinoma. Conclusion: SNPs-TPD were superior in drug solubility and oral bioavailability than those obtained from TPD suspension.
• Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines
  作者：Mohamed S.H. Salem、Yasmine M. Abdel Aziz、Mohamed S. Elgawish、Mohamed M. Said、Khaled A.M. Abouzid

  DOI：10.1016/j.bioorg.2019.103472

  日期：2020.1

  Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs) this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANG-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 mu M. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-alpha) inhibitory activity, with IC50 value 0.155 mu M. Docking study was carried out into PDGFR-alpha active site which showed comparable binding mode to that of FDA approved PDGFR-alpha inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.