(E)-5,5-bis(hydroxymethyl)-3-(1-decylidene)-4,5-dihydrofuran-2-one | 261357-40-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (E)-5,5-bis(hydroxymethyl)-3-(1-decylidene)-4,5-dihydrofuran-2-one
• 英文别名: (E)-5,5-bis(hydroxymethyl)-3-decylidene-4,5-dihydrofuran-2-one；(E)-5,5-bis(hydroxymethyl)-3-decylideneoxolan-2-one；(3E)-3-decylidene-5,5-bis(hydroxymethyl)oxolan-2-one
• CAS: 261357-40-8
• 化学式: C₁₆H₂₈O₄
• 分子量: 284.396
• InChiKey: DFQBQAIBGRFXDB-GXDHUFHOSA-N

物化性质

• 沸点：
  448.4±30.0 °C(Predicted)
• 密度：
  1.089±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  20
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  环己甲酰氯 、 (E)-5,5-bis(hydroxymethyl)-3-(1-decylidene)-4,5-dihydrofuran-2-one 在 4 A molecular sieve 、 二正丁基氧化锡 作用下， 以 甲苯 为溶剂， 反应 3.5h， 以90%的产率得到(E)-[4-decylidene-2-(hydroxymethyl)-5-oxo-2,3-dihydrofur-2-yl]methyl cyclohexanecarboxylate
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol. 26. Exploring the Chemical Space Surrounding the C1 Domain of Protein Kinase C with DAG-Lactones Containing Aryl Groups at the sn-1 and sn-2 Positions

  摘要：

  Diacylglycerol lactones (DAG-lactones) are known to operate as effective agonists of protein kinase C (PKC), surpassing in potency the activity of natural diacylglycerol (DAG). Localization of activated PKC isozymes in the cell is determined in part by the different cellular scaffolds, the lipid composition of the specific membranes, and the targeting information intrinsic to the individual isoforms bound to DAG. This multifaceted control of diversity suggests that, to develop effective DAG-lactones capable of honing in on a specific cellular target, we need to gain a better understanding of the chemical space surrounding its binding site. Seeking to augment the chemical repertoire of DAG-lactone side chains that could steer the translocation of PKC to specific cellular domains, we report herein the effects of incorporating simple or substituted phenyl residues. A combined series of n-alkyl and phenyl substitutions were used to explore the optimal location of the phenyl group on the side chains. The substantial differences in binding affinity between DAG-lactones with identical functionalized phenyl groups at either the sn-1 or sn-2 position are consistent with the proposed binding model in which the DAG-lactone binds to the C1 domain of PKC with the acyl chain oriented toward the interior of the membrane and the alpha-alkylidene or alpha-arylalkylidene chains directed to the surface of the C1 domain adjacent to the lipid interface. We conclude that DAG-lactones containing alpha-phenylalkylidene side chains at the sn-2 position represent excellent scaffolds upon which to explore further chemical diversity.

  DOI：

  10.1021/jm060011o
• 作为产物：
  描述：

  5-bis<<(tert-butyldiphenylsilyl)oxy>methyl>tetrahydro-2-furanone 在 吡啶 、 氢氟酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正庚烷 、 二氯甲烷 、 乙基苯 为溶剂， 反应 8.5h， 生成 (E)-5,5-bis(hydroxymethyl)-3-(1-decylidene)-4,5-dihydrofuran-2-one
  参考文献：
  名称：

  构象受限的二酰基甘油（DAG）类似物。16.识别和对蛋白激酶C的高结合亲和力需要多少结构复杂性？

  摘要：

  具有低纳摩尔结合亲和力的有效蛋白激酶C（PK-C）配体的设计是通过结合使用基于生理酶激活剂二酰基甘油（DAG）的药效基团和受体指导的方法来完成的。以前使用基于DAG和佛波酯酯药效基团的结构等效性的方法，确定了用于构建半刚性“识别域”的固定模板，该模板包含受限制在内酯环（DAG）中的DAG的三个主要药效基团。 -内酯）。在目前的工作中，基于与佛波醇13-O-乙酸酯复合的PK-Cdelta C1b结构域的X射线结构，将药效团引导的方法改进到了更高的水平。一个系统的搜索，涉及用线性或支链酰基和α-亚烷基链的组合修饰DAG-内酯模板，它们起可变的疏水“亲和结构域”的作用，帮助鉴定了优化与一组保守的疏水氨基酸的疏水接触的化合物位于佛波结合的C1域的上半部分。分子的亲水/疏水平衡通过根据基于片段的方法计算出的辛醇/水分配系数（log P）进行估算。支链α-亚烷基或酰基链的存在对于达到PK-C的低纳摩尔

  DOI：

  10.1021/jm9904607

文献信息

• Conformationally Constrained Analogues of Diacylglycerol (DAG). 16. How Much Structural Complexity Is Necessary for Recognition and High Binding Affinity to Protein Kinase C?
  作者：Kassoum Nacro、Bruno Bienfait、Jeewoo Lee、Kee-Chung Han、Ji-Hye Kang、Samira Benzaria、Nancy E. Lewin、Dipak K. Bhattacharyya、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm9904607

  日期：2000.3.1

  modifying the DAG-lactone template with a combination of linear or branched acyl and alpha-alkylidene chains, which functioned as variable hydrophobic "affinity domains", helped identify compounds that optimized hydrophobic contacts with a group of conserved hydrophobic amino acids located on the top half of the C1 domain where the phorbol binds. The hydrophilic/hydrophobic balance of the molecules was estimated

  具有低纳摩尔结合亲和力的有效蛋白激酶C（PK-C）配体的设计是通过结合使用基于生理酶激活剂二酰基甘油（DAG）的药效基团和受体指导的方法来完成的。以前使用基于DAG和佛波酯酯药效基团的结构等效性的方法，确定了用于构建半刚性“识别域”的固定模板，该模板包含受限制在内酯环（DAG）中的DAG的三个主要药效基团。 -内酯）。在目前的工作中，基于与佛波醇13-O-乙酸酯复合的PK-Cdelta C1b结构域的X射线结构，将药效团引导的方法改进到了更高的水平。一个系统的搜索，涉及用线性或支链酰基和α-亚烷基链的组合修饰DAG-内酯模板，它们起可变的疏水“亲和结构域”的作用，帮助鉴定了优化与一组保守的疏水氨基酸的疏水接触的化合物位于佛波结合的C1域的上半部分。分子的亲水/疏水平衡通过根据基于片段的方法计算出的辛醇/水分配系数（log P）进行估算。支链α-亚烷基或酰基链的存在对于达到PK-C的低纳摩尔
• Conformationally Constrained Analogues of Diacylglycerol. 21. A Solid-Phase Method of Synthesis of Diacylglycerol Lactones as a Prelude to a Combinatorial Approach for the Synthesis of Protein Kinase C Isozyme-Specific Ligands
  作者：Dehui Duan、Nancy E. Lewin、Dina M. Sigano、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm030610k

  日期：2004.6.1

  R(2)COCl introduced the second element of diversity. Acid-assisted cleavage of the compounds from the resin afforded the final targets. The biological results obtained using the crude samples directly obtained from the resin compared well with those from pure materials, as the K(i) values between the two sets varied only by a factor between 1.5 and 3.7.

  开发了一种固相合成二酰基甘油内酯作为蛋白激酶C配体的方法，并选择了9种化合物的一小部分，以测试这种方法并预测生物学数据的可靠性，以此作为构建PPAR的前言。在相同条件下可以合成的大型化学文库。该方法开始于将5-（羟甲基）-5-[（4-甲氧基苯氧基）甲基] -3,4,5-三氢呋喃-2-酮（1）加载到3,4-二氢-2H-吡喃树脂中装在IRORI MacroKan反应堆中。分别使用三种不同的醛和三种不同的酰氯在α-亚烷基（R（1））和酰基（R（2））位置引入多样性元素。在ZnCl（2）存在下用R（1）CHO进行LDA介导的羟醛缩合，然后DBU催化消除所得羟醛的三氟甲磺酸酯，得到α-亚烷基中间体，为几何异构体的混合物。除去芳基保护基，然后用R（2）COCl酰化，引入了多样性的第二个要素。化合物从树脂上的酸辅助裂解提供了最终的靶标。使用直接从树脂获得的粗样品与纯材料得到的生物学结果进行了很好的比较，因为两组之间的K（i）值仅在1
• Conformationally Constrained Analogues of Diacylglycerol. 26. Exploring the Chemical Space Surrounding the C1 Domain of Protein Kinase C with DAG-Lactones Containing Aryl Groups at the <i>sn</i>-1 and <i>sn</i>-2 Positions
  作者：Ji-Hye Kang、Samira Benzaria、Dina M. Sigano、Nancy E. Lewin、Yongmei Pu、Megan L. Peach、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm060011o

  日期：2006.6.1

  Diacylglycerol lactones (DAG-lactones) are known to operate as effective agonists of protein kinase C (PKC), surpassing in potency the activity of natural diacylglycerol (DAG). Localization of activated PKC isozymes in the cell is determined in part by the different cellular scaffolds, the lipid composition of the specific membranes, and the targeting information intrinsic to the individual isoforms bound to DAG. This multifaceted control of diversity suggests that, to develop effective DAG-lactones capable of honing in on a specific cellular target, we need to gain a better understanding of the chemical space surrounding its binding site. Seeking to augment the chemical repertoire of DAG-lactone side chains that could steer the translocation of PKC to specific cellular domains, we report herein the effects of incorporating simple or substituted phenyl residues. A combined series of n-alkyl and phenyl substitutions were used to explore the optimal location of the phenyl group on the side chains. The substantial differences in binding affinity between DAG-lactones with identical functionalized phenyl groups at either the sn-1 or sn-2 position are consistent with the proposed binding model in which the DAG-lactone binds to the C1 domain of PKC with the acyl chain oriented toward the interior of the membrane and the alpha-alkylidene or alpha-arylalkylidene chains directed to the surface of the C1 domain adjacent to the lipid interface. We conclude that DAG-lactones containing alpha-phenylalkylidene side chains at the sn-2 position represent excellent scaffolds upon which to explore further chemical diversity.