6-[2-(ethoxycarbonyl)methyl]-9-(tetrahydropyran-2-yl)-9H-purine | 948037-39-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 6-[2-(ethoxycarbonyl)methyl]-9-(tetrahydropyran-2-yl)-9H-purine
• 英文别名: Ethyl 2-[9-(oxan-2-yl)purin-6-yl]acetate；ethyl 2-[9-(oxan-2-yl)purin-6-yl]acetate
• CAS: 948037-39-6
• 化学式: C₁₄H₁₈N₄O₃
• 分子量: 290.322
• InChiKey: CRIGXQMWSZGEFX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  79.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-[2-(ethoxycarbonyl)methyl]-9-(tetrahydropyran-2-yl)-9H-purine 在 Dowex 50 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以93%的产率得到6-氯嘌呤
  参考文献：
  名称：

  通过6-氯嘌呤与Reformatsky试剂的交叉偶联合成（嘌呤-6-基）乙酸酯和6-（2-羟乙基）嘌呤

  摘要：

  基于6-氯嘌呤与Reformatsky试剂在Pd催化的交叉偶联反应，然后经NaBH 4还原和MnO 2处理的基础上，开发了一种新型的6-（2-羟乙基）嘌呤合成方法。该方法已成功应用于6-（乙氧基羰基甲基）-和6-（羟乙基）嘌呤碱基和核苷的合成。

  DOI：

  10.1016/j.tetlet.2007.06.053
• 作为产物：
  描述：

  2-[9-[tetrahydro-2H-pyran-2-yl]-9H-purin-6-yl]propanedioic acid diethyl ester 在 sodium ethanolate 作用下， 以 乙醇 为溶剂， 反应 2.5h， 以92.4%的产率得到6-[2-(ethoxycarbonyl)methyl]-9-(tetrahydropyran-2-yl)-9H-purine
  参考文献：
  名称：

  Potent Pan-Raf and Receptor Tyrosine Kinase Inhibitors Based on a Cyclopropyl Formamide Fragment Overcome Resistance

  摘要：

  While selective BRaf(V600E) inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway, Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs). Based on the binding mode of I-01, analogues I-02-1-18 were designed and synthesized. The most promising compound I-16 potently inhibits subtypes of Rafs with IC50 values of 3.49 (BRaf(V600E)), 8.86 (ARaf), 5.78 (BRaf(WT)), and 1.65 nM (CRaf); respectively. I-16 not only exhibit comparable antiproliferative activities with positive control compounds against HepG2, SW579, MV4-11, and COLO205 cell lines, but also suppress the proliferation of melanoma SK-MEL-2 harboring overexpressed BRaf(WT) with IC50 values of 0.93 mu M. The Western blot results for: the ERK inhibition in human melanoma SK-MEL-2 cell lines show that I-16 inhibits the proliferation of SK-MEL-2 cell lines without paradoxical activation of ERK, which support the hypothesis that the inhibition of Pan-Raf and RTKs might be a tractable strategy to overcome the resistance of melanoma induced by the therapy with the current selective BRar(V600E) inhibitors..

  DOI：

  10.1021/acs.jcim.6b00795

文献信息

• Synthesis of (purin-6-yl)acetates and their transformations to 6-(2-hydroxyethyl)- and 6-(carbamoylmethyl)purines
  作者：Zbyněk Hasník、Radek Pohl、Blanka Klepetářová、Michal Hocek

  DOI：10.1135/cccc2009042

  日期：——

  A novel approach to the synthesis of (purin-6-yl)acetates was developed based on Pd-catalyzed cross-coupling reactions of 6-chloropurines with a Reformatsky reagent. Their reduction with NaBH₄ and treatment with MnO₂ gave 6-(2-hydroxyethyl)purines, while reactions with amines in presence of NaCN afforded 6-(carbamoylmethyl)purines. Mesylation of the 6-(2-hydroxyethyl)purines followed by nucleophilic substitutions gave rise to several 6-(2-substituted ethyl)purines. This methodology was successfully applied to the synthesis of substituted purine bases and nucleosides for cytostatic and antiviral activity screening. None of the compounds exerted significant activity.

  基于Pd催化的6-氯嘌呤与Reformatsky试剂的交叉偶联反应，开发了一种合成(purin-6-yl)乙酸酯的新方法。它们经过NaBH₄还原和MnO₂处理后，形成6-(2-羟乙基)嘌呤，而与胺在NaCN存在下反应则得到6-(carbamoylmethyl)嘌呤。6-(2-羟乙基)嘌呤的Mesylation后，进行亲核取代反应，可以得到多种6-(2-取代乙基)嘌呤。这种方法成功地应用于合成替代嘌呤碱基和核苷，用于细胞毒和抗病毒活性筛选。但是，这些化合物均未表现出显著的活性。
• Potent Pan-Raf and Receptor Tyrosine Kinase Inhibitors Based on a Cyclopropyl Formamide Fragment Overcome Resistance
  作者：Yanmin Zhang、Lu Wang、Qing Zhang、Gaoyuan Zhu、Zhimin Zhang、Xiang Zhou、Yadong Chen、Tao Lu、Weifang Tang

  DOI：10.1021/acs.jcim.6b00795

  日期：2017.6.26

  While selective BRaf(V600E) inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway, Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs). Based on the binding mode of I-01, analogues I-02-1-18 were designed and synthesized. The most promising compound I-16 potently inhibits subtypes of Rafs with IC50 values of 3.49 (BRaf(V600E)), 8.86 (ARaf), 5.78 (BRaf(WT)), and 1.65 nM (CRaf); respectively. I-16 not only exhibit comparable antiproliferative activities with positive control compounds against HepG2, SW579, MV4-11, and COLO205 cell lines, but also suppress the proliferation of melanoma SK-MEL-2 harboring overexpressed BRaf(WT) with IC50 values of 0.93 mu M. The Western blot results for: the ERK inhibition in human melanoma SK-MEL-2 cell lines show that I-16 inhibits the proliferation of SK-MEL-2 cell lines without paradoxical activation of ERK, which support the hypothesis that the inhibition of Pan-Raf and RTKs might be a tractable strategy to overcome the resistance of melanoma induced by the therapy with the current selective BRar(V600E) inhibitors..
• Synthesis of (purin-6-yl)acetates and 6-(2-hydroxyethyl)purines via cross-couplings of 6-chloropurines with the Reformatsky reagent
  作者：Zbyněk Hasník、Peter Šilhár、Michal Hocek

  DOI：10.1016/j.tetlet.2007.06.053

  日期：2007.8

  A novel approach to the synthesis of 6-(2-hydroxyethyl)purines was developed based on Pd-catalyzed cross-coupling reactions of 6-chloropurines with the Reformatsky reagent followed by reduction by NaBH4 and treatment with MnO2. This methodology was successfully applied to the syntheses of 6-(ethoxycarbonylmethyl)- and 6-(hydroxyethyl)purine bases and nucleosides.

  基于6-氯嘌呤与Reformatsky试剂在Pd催化的交叉偶联反应，然后经NaBH 4还原和MnO 2处理的基础上，开发了一种新型的6-（2-羟乙基）嘌呤合成方法。该方法已成功应用于6-（乙氧基羰基甲基）-和6-（羟乙基）嘌呤碱基和核苷的合成。