2-<3-Chlor-phenyl>-4-hydroxy-4-methyl-6-oxo-cyclohexan-1,3-dicarbonsaeure-diethylester | 4759-55-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-<3-Chlor-phenyl>-4-hydroxy-4-methyl-6-oxo-cyclohexan-1,3-dicarbonsaeure-diethylester
• 英文别名: Diethyl 2-(3-chlorophenyl)-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate
• CAS: 4759-55-1
• 化学式: C₁₉H₂₃ClO₆
• mdl: MFCD00785410
• 分子量: 382.841
• InChiKey: QRUWDFCYKJYGTR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.526
• 拓扑面积：
  89.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-<3-Chlor-phenyl>-4-hydroxy-4-methyl-6-oxo-cyclohexan-1,3-dicarbonsaeure-diethylester 在 乙酰氯 、 sodium hydroxide 作用下， 反应 4.0h， 生成 3-<3-Chlor-phenyl>-glutarsaeure-anhydrid
  参考文献：
  名称：

  4-Benzimidazolyl-3-Phenylbutanoic Acids As Novel Pif-Pocket-Targeting Allosteric Inhibitors of Protein Kinase PKCζ

  摘要：

  Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) zeta via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKC zeta, lacking inhibition of the most closely related isoform, PKCl, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKC zeta without loss of potency compared to the cell-free assay.

  DOI：

  10.1021/jm2005892
• 作为产物：
  描述：

  乙酰乙酸乙酯 、 3-氯苯甲醛 在 哌嗪 作用下， 以 乙醇 为溶剂， 反应 0.17h， 生成 2-<3-Chlor-phenyl>-4-hydroxy-4-methyl-6-oxo-cyclohexan-1,3-dicarbonsaeure-diethylester
  参考文献：
  名称：

  Effect of Aryl-Cyclohexanones and their Derivatives on Macrophage Polarization In Vitro

  摘要：

  巨噬细胞在组织稳态和炎症过程中都起着至关重要的作用，其极化的变化被认为是解决炎症过程的关键。炎症是免疫反应的一个复杂而必要的组成部分，它针对的是对宿主稳态有害的刺激，并受到细胞和分子事件的调节，而这些事件仍是研究的一个来源。在已研究的具有抗自身免疫性和炎症性疾病潜力的化合物中，大麻素是目前研究的重点。本研究以大麻二酚（CBD）等植物大麻素的芳基环己烷骨架为基础，合成了 19 种芳基环己酮二酯及其衍生物，并对其抗炎和巨噬细胞极化潜力进行了评估。结果表明，化合物 4 能抑制 RAW 264.7 巨噬细胞产生一氧化氮。此外，它还能降低促炎细胞因子 IL-12p70、TNF-α、IFN-γ、MCP-1 和 IL-6 的水平，同时还能增加抗炎细胞因子 IL-4、IL-10 和 IL-13 的产生。化合物 4 还能减少巨噬细胞凋亡，增加这些细胞表面 CD206（甘露糖受体）的表达，同时减少 CD284（TLR-4 受体）的表达。最后，它还提高了吞噬能力，抑制了 NF-kβ 的 p65 的磷酸化。总之，被鉴定为二乙基-4-羟基-2-（4-甲氧基苯基）-4-甲基-6-氧代环己烷-1-3-二甲酸酯的化合物 4 显示出了显著的抗炎效果，同时还显示出了将巨噬细胞从 M1 表型（促炎）转化为 M2 表型（抗炎）的能力。由此我们推测，该分子抗炎作用的主要机制与其免疫调节能力有关。

  DOI：

  10.1007/s10753-022-01646-9

文献信息

• A Facile Synthesis of 4-Aryl-5-alkoxycarbonyl- 6-hydroxy-6-methyl-4,5,6,7-tetrahydro- 3-hydroxy-2-(pyridin-2-yl)indazoles and Their NMR Characterizations
  作者：Yeon Tae Jeong、Shanmugasundaram Amirthaganesan、Gopalakrishnan Aridoss、Young Hwan Park、Jong Su Kim、Se Mo Son

  DOI：10.3987/com-07-11231

  日期：——
• 4-Benzimidazolyl-3-Phenylbutanoic Acids As Novel Pif-Pocket-Targeting Allosteric Inhibitors of Protein Kinase PKCζ
  作者：Wolfgang Fröhner、Laura A. Lopez-Garcia、Sonja Neimanis、Nadja Weber、Jeanette Navratil、Frauke Maurer、Adriana Stroba、Hua Zhang、Ricardo M. Biondi、Matthias Engel

  DOI：10.1021/jm2005892

  日期：2011.10.13

  Protein kinase inhibitors with an allosteric mode of action are expected to reach, in many cases, higher selectivity for the target enzyme than ATP-competitive compounds. Therefore, basic research is aiming at identifying and establishing novel sites on the catalytic domain of protein kinases which might be targeted by allosteric inhibitors. We previously published the first structure-activity relationships (SARs) for allosteric activators of protein kinase PDK1. Here, we present the design, synthesis, and SAR data on a series of novel compounds, 4-benzimidazolyl-3-phenylbutanoic acids, that inhibit the atypical protein kinace C (PKC) zeta via binding to the PIF-pocket. Key positions were identified in the compounds that can be modified to increase potency and selectivity. Some congeners showed a high selectivity toward PKC zeta, lacking inhibition of the most closely related isoform, PKCl, and of further AGC kinases. Furthermore, evidence is provided that these compounds are also active toward cellular PKC zeta without loss of potency compared to the cell-free assay.
• Effect of Aryl-Cyclohexanones and their Derivatives on Macrophage Polarization In Vitro
  作者：Tainá L. Lubschinski、Luiz A. E. Pollo、Eduarda T. B. Mohr、Julia S. da Rosa、Luigi A. Nardino、Louis P. Sandjo、Maique W. Biavatti、Eduardo M. Dalmarco

  DOI：10.1007/s10753-022-01646-9

  日期：2022.8

  Macrophages are critical in both tissue homeostasis and inflammation, and shifts in their polarization have been indicated as pivotal for the resolution of inflammatory processes. Inflammation is a complex and necessary component of the immune response to stimuli that are harmful to host homeostasis and is regulated by cellular and molecular events that remain a source of ongoing investigation. Among the compounds studied that have potential against autoimmune and inflammatory diseases, cannabinoids are currently highlighted. In this work, nineteen aryl-cyclohexanones diesters and their derivatives were synthesized based on the aryl-cyclohexane skeleton of phytocannabinoids, such as cannabidiol (CBD), and were evaluated for their anti-inflammatory and macrophage polarization potential. The results showed that Compound 4 inhibited the production of nitric oxide in RAW 264.7 macrophages. Furthermore, it reduced the levels of pro-inflammatory cytokines IL-12p70, TNF-α, IFN-γ, MCP-1, and IL-6 while, at the same time, was able to increase the production of anti-inflammatory cytokines IL-4, IL-10, and IL-13. Compound 4 also reduced macrophage apoptosis, increased the expression of the CD206 (mannose receptor) and at the same time, decreased the expression of CD284 (TLR-4 receptor) on the surface of these cells. Finally, it increased the phagocytic capacity and inhibited the phosphorylation of the p65 of NF-kβ. In conclusion, Compound 4, identified as diethyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-6-oxocyclohexane-1–3-dicarboxylate, showed significant anti-inflammatory effect, while demonstrating the ability to transform phenotypically macrophages from the M1 phenotype (pro-inflammatory) to the M2 phenotype (anti-inflammatory). This led us to hypothesize that the main mechanism of anti-inflammatory effect of this molecule is linked to its immune modulation capacity.

  巨噬细胞在组织稳态和炎症过程中都起着至关重要的作用，其极化的变化被认为是解决炎症过程的关键。炎症是免疫反应的一个复杂而必要的组成部分，它针对的是对宿主稳态有害的刺激，并受到细胞和分子事件的调节，而这些事件仍是研究的一个来源。在已研究的具有抗自身免疫性和炎症性疾病潜力的化合物中，大麻素是目前研究的重点。本研究以大麻二酚（CBD）等植物大麻素的芳基环己烷骨架为基础，合成了 19 种芳基环己酮二酯及其衍生物，并对其抗炎和巨噬细胞极化潜力进行了评估。结果表明，化合物 4 能抑制 RAW 264.7 巨噬细胞产生一氧化氮。此外，它还能降低促炎细胞因子 IL-12p70、TNF-α、IFN-γ、MCP-1 和 IL-6 的水平，同时还能增加抗炎细胞因子 IL-4、IL-10 和 IL-13 的产生。化合物 4 还能减少巨噬细胞凋亡，增加这些细胞表面 CD206（甘露糖受体）的表达，同时减少 CD284（TLR-4 受体）的表达。最后，它还提高了吞噬能力，抑制了 NF-kβ 的 p65 的磷酸化。总之，被鉴定为二乙基-4-羟基-2-（4-甲氧基苯基）-4-甲基-6-氧代环己烷-1-3-二甲酸酯的化合物 4 显示出了显著的抗炎效果，同时还显示出了将巨噬细胞从 M1 表型（促炎）转化为 M2 表型（抗炎）的能力。由此我们推测，该分子抗炎作用的主要机制与其免疫调节能力有关。