ethyl 1,2,3,4-tetrahydro-6-methyl-4-(pyridine-3-yl)-2-thioxopyrimidine-5-carboxylate | 123629-47-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: ethyl 1,2,3,4-tetrahydro-6-methyl-4-(pyridine-3-yl)-2-thioxopyrimidine-5-carboxylate
• 英文别名: ethyl 4-(pyridin-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate；ethyl 6-methyl-4-(pyridin-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate；ethyl 4-(3-pyridyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate；Ethyl 6-methyl-4-pyridin-3-yl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate；ethyl 6-methyl-4-pyridin-3-yl-2-sulfanylidene-3,4-dihydro-1H-pyrimidine-5-carboxylate
• CAS: 123629-47-0
• 化学式: C₁₃H₁₅N₃O₂S
• 分子量: 277.347
• InChiKey: JPYRFQAGJBOJFZ-UHFFFAOYSA-N

物化性质

• 熔点：
  75-79 °C(Solv: methanol (67-56-1))
• 沸点：
  409.1±55.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  95.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-溴-2,4-二甲氧基苯甲醛 、 ethyl 1,2,3,4-tetrahydro-6-methyl-4-(pyridine-3-yl)-2-thioxopyrimidine-5-carboxylate 、 氯乙酸 在 sodium acetate 、 溶剂黄146 作用下， 以 乙酸酐 为溶剂， 反应 9.0h， 以5.1%的产率得到(Z)-ethyl 2-(5-bromo-2,4-dimethoxybenzylidene)-5-(pyridin-3-yl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate
  参考文献：
  名称：

  Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor

  摘要：

  Protein kinase casein kinase 2 (PKCK2) is a constitutively active, growth factor-independent serine/threonine kinase, and changes in PKCK2 expression or its activity are reported in many cancer cells. To develop a novel PKCK2 inhibitor(s), we first performed cell-based phenotypic screening using 4000 chemicals purchased from ChemDiv chemical libraries (2000: randomly selected; 2000: kinase-biased) and performed in vitro kinase assay-based screening using hits found from the first screening. We identified compound 24 (C24)[(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carboxylate] as a novel inhibitor of PKCK2 that is more potent and selective than 4,5,6,7-tetrabromobenzotriazole (TBB). In particular, compound 24 [half maximal inhibitory concentration (IC50)=0.56μM] inhibited PKCK2 2.2-fold more efficiently than did TBB (IC50=1.24μM), which is quite specific toward PKCK2 with respect to ATP binding, in a panel of 31 human protein kinases. The Ki values of compound 24 and TBB for PKCK2 were 0.78μM and 2.70μM, respectively. Treatment of cells with compound 24 inhibited endogenous PKCK2 activity and showed anti-proliferative and pro-apoptotic effects against stomach and hepatocellular cancer cell lines more efficiently than did TBB. As expected, compound 24 also enabled tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-resistant cancer cells to be sensitive toward TRAIL. In comparing the molecular docking of compound 24 bound to PKCK2α versus previously reported complexes of PKCK2 with other inhibitors, our findings suggest a new scaffold for specific PKCK2α inhibitors. Thus, compound 24 appears to be a selective, cell-permeable, potent, and novel PKCK2 inhibitor worthy of further characterization.

  DOI：

  10.1016/j.bmc.2014.07.037
• 作为产物：
  描述：

  3-吡啶甲醛 、 乙酰乙酸乙酯 、 硫脲 在 C₁₀H₄O₈^(2-)*Ca⁽²⁺⁾*C₃H₇NO*H₂O 作用下， 以 乙醇 为溶剂， 以92 %的产率得到ethyl 1,2,3,4-tetrahydro-6-methyl-4-(pyridine-3-yl)-2-thioxopyrimidine-5-carboxylate
  参考文献：
  名称：

  钙基金属有机框架中羧酸含量对增强 Biginelli 反应的作用

  摘要：

  金属有机框架 （MOF） 可以携带不同的官能团，例如 COOH、NH2 和 SO3H。最常用的官能团是 COOH，因为它具有 Brønsted 酸度、极性以及通过各种相互作用与有机化合物和金属键合的能力。在这里，成功制备了具有不同羧基臂的钙基 MOFs （Ca-MOFs） 并用于多相 Biginelli 催化反应。使用不同的光谱技术对制备的材料 （Ca-BDC-H、Ca-BDC-COOH 和 Ca-BDC-（COOH）2） 进行表征，并使用显微分析确定形态结构。除了阐明 MOF 的精细形式外，还测试了羧酸含量在不同动力学和热力学研究的多组分反应催化中的作用，使用 NMR 分析确定了催化产物的形成，并研究了所提出的机制。获得的结果表明，随着网络中羧酸含量的增加，催化反应产率增加，这可以支持在非均相催化剂中使用网络中存在的具有酸性特性的 COOH 基团的可能性，从而获得高产品产率。

  DOI：

  10.1016/j.molstruc.2024.139742

文献信息

• Green synthesis and 3D pharmacophore study of pyrimidine and glucoside derivatives with in vitro potential anticancer and antioxidant activities
  作者：Mounir A. Salem、Mohamed S. Behalo、Eman Elrazaz

  DOI：10.1007/s00044-019-02367-9

  日期：2019.8

  facile and an efficient one-pot green synthesis of pyrimidine derivatives using the environmentally friendly Cerium(IV) ammonium nitrate (CAN) as catalyst and water as a solvent has been described. Some of the synthesized pyrimidines react with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide in ethanol containing potassium hydroxide to give S-glucoside derivatives. The structures of the newly synthesized

  已经描述了使用环境友好的硝酸铈（IV）铵（CAN）作为催化剂和水作为溶剂的嘧啶衍生物的便捷且有效的一锅绿色合成。在含有氢氧化钾的乙醇中，一些合成的嘧啶与2,3,4,6-四-O-乙酰基-α- d-吡喃葡萄糖基溴化物反应，得到S-葡萄糖苷衍生物。根据其光谱和元素分析，阐明了新合成的化合物的结构。此外，使用MTT分析法筛选了产品的选定衍生物对四种肿瘤细胞系的抗癌活性，结果表明，其中某些化合物具有有效的细胞毒性作用，由其IC 50得出结论价值观。进行了分子建模研究，包括生成3D药效团模型。该研究表明与实验结果高度相关。还研究了合成产物的抗氧化活性，其中大多数显示出有效的活性。
• Dihydropyrimidine-2-thiones as Eg5 inhibitors and L-type calcium channel blockers: potential antitumour dual agents
  作者：Elena González-Hernández、Rubén Aparicio、Mercedes Garayoa、M. José Montero、M. Ángeles Sevilla、Concepción Pérez-Melero

  DOI：10.1039/c9md00108e

  日期：——

  4-Aryldihydropyrimidine-2-thiones are proposed as potential antitumour dual agents, both as Eg5 inhibitors and L-type calcium channel blockers.

  4-芳基二氢嘧啶-2-硫酮被提议作为潜在的抗肿瘤双重作用剂，既是Eg5抑制剂又是L型钙通道阻滞剂。
• Monastrol, a 3,4-dihydropyrimidin-2(1 H )-thione, as structural scaffold for the development of modulators for GHB high-affinity binding sites and α 1 β 2 δ GABA A receptors
  作者：Maria Damgaard、Anas Al-Khawaja、Mia Nittegaard-Nielsen、Rebekka F. Petersen、Petrine Wellendorph、Bente Frølund

  DOI：10.1016/j.ejmech.2017.06.024

  日期：2017.9

  The (alpha(4)beta delta subtype of the gamma-aminobutyric acid (GABA) type A receptors (GABA(A)Rs) has been shown to be implicated in high-affinity binding of the neuromodulator gamma-hydroxybutyric acid (GHB), but may not be the only GHB high-affinity binding sites. Monastrol has been identified as a modulator of GHB high affinity binding and is furthermore reported as an allosteric modulator selective for the alpha(1)beta(2)delta GABAARs. Therefore, structural determinants for selectivity at the two targets were investigated. 39 structural diverse monastrol analogues were synthesized by employing the Biginelli cyclocondensation and examined for modulation of GHB high-affinity binding using the GHB-specific ligand [H-3]NCS-382 [(E,RS)=6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid] in rat brain homogenate. Only limited modifications were allowed on the monastrol scaffold in order to maintain modulation of GHB high-affinity binding. However, three analogues of monastrol (11,12 and 24) enhanced the maximal binding of [H-3]NCS-382 to a higher maximal level than seen for monastrol itself. Selected compounds were further characterized as modulators at alpha(1)beta(2)delta, alpha(1)beta(2)gamma(2s) and alpha(1)beta(2) GABA(A)Rs. Most of these modulators were shown to have delta-specific GABA-potentiating effects. The dual effect shown for monastrol to modulate the GHB high-affinity binding and alpha(1)beta(2)delta GABA(A)R activity was also shown for the compounds 11, 18 and 24. Compound 29 displayed minimal modulatory effect on GABA(A)Rs and therefore appears to be a GHB high-affinity binding preferring modulator. However, compounds 34 and 37 were shown to be alpha(1)beta(2)delta GABA(A)R selective modulators, without modulatory effects on GHB high-affinity binding. Thus, our study shows that minor modifications in the structure of monastrol affects the selectivity profile for the two targets under study enabling separation of the dual activity. (C) 2017 Elsevier Masson SAS. All rights reserved.
• Synthesis and Inhibitory Activity Against Epstein-Barr Virus of Some New 1,2,3,4-Tetrahydropyrimidine-2-thiones
  作者：Fawzy A. Attaby、Mostafa M. Ramla、T. Harukuni

  DOI：10.1080/10426500802043152

  日期：2008.11.7

  1,2,3,4-Tetrahydropyrimidine-2-thiones 4a-n were synthesized through the reaction of aromatic aldehydes 1a-n, ethyl acetoacetate (2) and thiourea (3). The structures of all newly synthesized heterocyclic compounds elucidated by the use of IR, 1H NMR, mass spectra, and elemental analyses. The inhibitory activity against the Epstein-Barr Virus early antigen (EBA-VA) of all newly synthesized heterocyclic compounds were evaluated.
• Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor
  作者：Cheng-Hao Jin、Kyu-Yeon Jun、Eunjung Lee、Seongrak Kim、Youngjoo Kwon、Kunhong Kim、Younghwa Na

  DOI：10.1016/j.bmc.2014.07.037

  日期：2014.9

  Protein kinase casein kinase 2 (PKCK2) is a constitutively active, growth factor-independent serine/threonine kinase, and changes in PKCK2 expression or its activity are reported in many cancer cells. To develop a novel PKCK2 inhibitor(s), we first performed cell-based phenotypic screening using 4000 chemicals purchased from ChemDiv chemical libraries (2000: randomly selected; 2000: kinase-biased) and performed in vitro kinase assay-based screening using hits found from the first screening. We identified compound 24 (C24)[(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carboxylate] as a novel inhibitor of PKCK2 that is more potent and selective than 4,5,6,7-tetrabromobenzotriazole (TBB). In particular, compound 24 [half maximal inhibitory concentration (IC50)=0.56μM] inhibited PKCK2 2.2-fold more efficiently than did TBB (IC50=1.24μM), which is quite specific toward PKCK2 with respect to ATP binding, in a panel of 31 human protein kinases. The Ki values of compound 24 and TBB for PKCK2 were 0.78μM and 2.70μM, respectively. Treatment of cells with compound 24 inhibited endogenous PKCK2 activity and showed anti-proliferative and pro-apoptotic effects against stomach and hepatocellular cancer cell lines more efficiently than did TBB. As expected, compound 24 also enabled tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-resistant cancer cells to be sensitive toward TRAIL. In comparing the molecular docking of compound 24 bound to PKCK2α versus previously reported complexes of PKCK2 with other inhibitors, our findings suggest a new scaffold for specific PKCK2α inhibitors. Thus, compound 24 appears to be a selective, cell-permeable, potent, and novel PKCK2 inhibitor worthy of further characterization.