diethyl 2-(1,3-bis(4-chlorophenyl)-3-oxopropyl)malonate | 848089-63-4

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物
• 英文名称: diethyl 2-(1,3-bis(4-chlorophenyl)-3-oxopropyl)malonate
• 英文别名: diethyl 2-[1,3-bis(4-chlorophenyl)-3-oxopropyl]malonate；Diethyl 2-[1,3-bis(4-chlorophenyl)-3-oxopropyl]-malonate；diethyl 2-[1,3-bis(4-chlorophenyl)-3-oxopropyl]propanedioate
• CAS: 848089-63-4
• 化学式: C₂₂H₂₂Cl₂O₅
• 分子量: 437.32
• InChiKey: RBGIGJRCIGRPNG-UHFFFAOYSA-N

物化性质

• 熔点：
  67 °C
• 沸点：
  543.0±50.0 °C(Predicted)
• 密度：
  1.264±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  69.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  diethyl 2-(1,3-bis(4-chlorophenyl)-3-oxopropyl)malonate 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 4.0h， 以74%的产率得到2-[1,3-bis(4-chlorophenyl)-3-oxopropyl]malonic acid
  参考文献：
  名称：

  2-(3-Oxo-1,3-diphenylpropyl)malonic Acids as Potent Allosteric Ligands of the PIF Pocket of Phosphoinositide-Dependent Kinase-1: Development and Prodrug Concept

  摘要：

  The protein kinase C-related kinase 2 (PRK2)interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, We describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3- diphenylprapyl)malonic acids as potent allosteric activators binding, to the PIF pocket: Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order Of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the pm pocket, The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1 Employing a prodrug strategy, we were able to corrroborate the novel mechanism of action in cells.

  DOI：

  10.1021/jm3010477
• 作为产物：
  描述：

  4-氯苯甲醛 在 sodium hydride 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 3.0h， 生成 diethyl 2-(1,3-bis(4-chlorophenyl)-3-oxopropyl)malonate
  参考文献：
  名称：

  2-(3-Oxo-1,3-diphenylpropyl)malonic Acids as Potent Allosteric Ligands of the PIF Pocket of Phosphoinositide-Dependent Kinase-1: Development and Prodrug Concept

  摘要：

  The protein kinase C-related kinase 2 (PRK2)interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, We describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3- diphenylprapyl)malonic acids as potent allosteric activators binding, to the PIF pocket: Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order Of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the pm pocket, The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1 Employing a prodrug strategy, we were able to corrroborate the novel mechanism of action in cells.

  DOI：

  10.1021/jm3010477

文献信息

• [EN] ALLOSTERIC PROTEIN KINASE MODULATORS<br/>[FR] MODULATEURS DE PROTÉINE KINASE ALLOSTÉRIQUE
  申请人：UNIV SAARLAND

  公开号：WO2010043711A1

  公开（公告）日：2010-04-22

  The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.

  该发明提供特定的小分子化合物，这些化合物能够变构调节AGC蛋白激酶的活性或调节Aurora家族蛋白激酶的蛋白-蛋白相互作用，提供这些化合物的制备方法，包含这些化合物的药物组合物，以及它们用于制备治疗和预防与AGC蛋白激酶或Aurora家族蛋白激酶异常活动相关疾病的药物的应用。
• ALLOSTERIC PROTEIN KINASE MODULATORS
  申请人：Engel Matthias

  公开号：US20120046307A1

  公开（公告）日：2012-02-23

  The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.

  本发明提供了特定的小分子化合物，它们通过变构调节AGC蛋白激酶的活性或调节Aurora家族蛋白激酶的蛋白质-蛋白质相互作用，其生产方法，包含该化合物的药物组合物，以及它们用于制备治疗和预防与AGC蛋白激酶或Aurora家族蛋白激酶异常活动相关疾病的药物的应用。
• Exploring bis-(amino)cyclopropenylidene as a non-covalent Brønsted base catalyst in conjugate addition reactions
  作者：Gurdeep Singh、Prithwish Goswami、Ramasamy Vijaya Anand

  DOI：10.1039/c7ob02882b

  日期：——

  utilised as a non-covalent Brønsted base catalyst in the 1,6-conjugate addition of carbon nucleophiles to p-QMs. This protocol makes it possible to access unsymmetrical diaryl- and triarylmethanes in good to excellent yields. Further, this catalyst was also explored in the 1,4-conjugate addition of carbon nucleophiles to enone systems.

  在碳亲核体向p -QMs的1,6-共轭加成中，双-（氨基）环丙烯基已被用作非共价布朗斯台德碱催化剂。该协议使得可以以良好的产率获得不对称的二芳基甲烷和三芳基甲烷。此外，还在将碳亲核试剂的1，4-共轭加成至烯酮体系中探索了该催化剂。
• Allosteric protein kinase modulators
  申请人：Engel Matthias

  公开号：US08912186B2

  公开（公告）日：2014-12-16

  The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.

  本发明提供了一种特定的小分子化合物，可以变构地调节AGC蛋白激酶和Aurora家族蛋白激酶的活性或调节它们之间的蛋白质相互作用，以及制备它们的方法、包含它们的制药组合物，以及它们用于制备治疗与AGC蛋白激酶或Aurora家族蛋白激酶异常活性相关的疾病的药物。
• Base- and sulfur-promoted oxidative lactonization of chalcone-acetate Michael adducts: access to pyran-2-ones
  作者：Cao Nguyen Nguyen、Duc Toan Nguyen、Ha An Tran、Dinh Hung Mac、Thi Thu Tram Nguyen、Pascal Retailleau、Thanh Binh Nguyen

  DOI：10.1039/d4ob00479e

  日期：——

  A cost-effective, practical, straightforward and scalable synthesis of α-pyrones via base- and sulfur-promoted annulation of phenylacetates and chalcones is reported. Generated in situ from the starting components by using dbu as a base catalyst, the Michael adducts underwent a smooth oxidative cyclization into 3,4,6-triaryl-2-pyranones upon heating with DABCO and sulfur in DMSO. Extension to malonate

  据报道，通过碱和硫促进的乙酸苯酯和查尔酮的环化，一种经济高效、实用、简单且可扩展的 α-吡喃酮合成方法。使用 dbu 作为碱催化剂，由起始组分原位生成迈克尔加合物，与 DABCO 和硫在 DMSO 中加热后，顺利氧化环化为 3,4,6-三芳基-2-吡喃酮。扩展为丙二酸酯代替乙酸苯酯得到4,6-二芳基-2-吡喃酮-2-羧酸酯。