Decanoic acid 2-hydroxymethyl-4-[3-isopropyl-4-methyl-pent-(Z)-ylidene]-5-oxo-tetrahydro-furan-2-ylmethyl ester

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: Decanoic acid 2-hydroxymethyl-4-[3-isopropyl-4-methyl-pent-(Z)-ylidene]-5-oxo-tetrahydro-furan-2-ylmethyl ester
• 英文别名: [(4E)-2-(hydroxymethyl)-4-(4-methyl-3-propan-2-ylpentylidene)-5-oxooxolan-2-yl]methyl decanoate
• 化学式: C₂₅H₄₄O₅
• 分子量: 424.621
• InChiKey: PKDPPGRNXLDXPE-KGENOOAVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  30
• 可旋转键数：
  16
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.84
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-[(2,2-dimethyl-1,1-diphenyl-1-silapropoxy)methyl]-5-[(phenylmethoxy)methyl]-3,4,5-trihydrofuran-2-one 在 吡啶 、 盐酸 、 二氯乙酸 、 四丙基高钌酸铵 、 dimethyl sulfide borane 、 4 A molecular sieve 、 DOWEX 50WX₈-200 、 potassium tert-butylate 、 四丁基氟化铵 、 三氯化硼 、 sodium hydride 、 二异丁基氢化铝 、 溶剂黄146 、 二甲基亚砜 、 N-甲基吗啉氧化物 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正庚烷 、 二氯甲烷 、 乙基苯 、 甲苯 、 乙腈 为溶剂， 反应 117.5h， 生成 Decanoic acid 2-hydroxymethyl-4-[3-isopropyl-4-methyl-pent-(Z)-ylidene]-5-oxo-tetrahydro-furan-2-ylmethyl ester
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol. 20. The Search for an Elusive Binding Site on Protein Kinase C through Relocation of the Carbonyl Pharmacophore Along the sn-1 Side Chain of 1,2-Diacylglycerol Lactones

  摘要：

  Previous studies with 1,2-diacylglycerol (DAG) lactones, which behave as high-affinity ligands for protein kinase C (PK-C), have established the importance of maintaining intact the pharmacophore triad of two carbonyl moieties (sn-1 and sn-2) and the primary alcohol. In addition, docking studies of DAG-lactones into an empty C1b receptor of PK-Cdelta (as it appears in complex with phorbol 13-O-acetate) have revealed that in either of the two possible binding alternatives (sn-1 or sn-2) only one carbonyl group of the DAG-lactone is involved in binding. Therefore, the unknown receptor for the orphaned carbonyl appears to lie outside the boundaries of this binary complex, possibly residing at the membrane or near the membrane-protein interface. A strategy to locate the optimal location of the unengaged carbonyl was conceived by utilizing a small group of DAG-lactones (1-4) with a highly branched chain adjacent to the sn-2 carbonyl such that sn-2 binding is favored. With these compounds, various locations of the sn-1 carbonyl along the side chain were tested for their binding affinity for PK-C. The results indicate that the location of the side chain sn-1 carbonyl in a DAG-lactone must have perfect mimicry to the sn-1 carbonyl of the parent DAG for it to display high binding affinity. A proposed model from this work is that the missing pharmacophore in the ternary complex, which includes the membrane, is close to the membrane-protein interface.

  DOI：

  10.1021/jm030454h

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. 20. The Search for an Elusive Binding Site on Protein Kinase C through Relocation of the Carbonyl Pharmacophore Along the <i>sn</i>-1 Side Chain of 1,2-Diacylglycerol Lactones
  作者：Hirokazu Tamamura、Dina M. Sigano、Nancy E. Lewin、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm030454h

  日期：2004.1.1

  Previous studies with 1,2-diacylglycerol (DAG) lactones, which behave as high-affinity ligands for protein kinase C (PK-C), have established the importance of maintaining intact the pharmacophore triad of two carbonyl moieties (sn-1 and sn-2) and the primary alcohol. In addition, docking studies of DAG-lactones into an empty C1b receptor of PK-Cdelta (as it appears in complex with phorbol 13-O-acetate) have revealed that in either of the two possible binding alternatives (sn-1 or sn-2) only one carbonyl group of the DAG-lactone is involved in binding. Therefore, the unknown receptor for the orphaned carbonyl appears to lie outside the boundaries of this binary complex, possibly residing at the membrane or near the membrane-protein interface. A strategy to locate the optimal location of the unengaged carbonyl was conceived by utilizing a small group of DAG-lactones (1-4) with a highly branched chain adjacent to the sn-2 carbonyl such that sn-2 binding is favored. With these compounds, various locations of the sn-1 carbonyl along the side chain were tested for their binding affinity for PK-C. The results indicate that the location of the side chain sn-1 carbonyl in a DAG-lactone must have perfect mimicry to the sn-1 carbonyl of the parent DAG for it to display high binding affinity. A proposed model from this work is that the missing pharmacophore in the ternary complex, which includes the membrane, is close to the membrane-protein interface.