(Z)-5-bis-(hydroxymethyl)-3-(tetradecanylidene)-tetrahydro-2-furanone | 172843-20-8

• 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: (Z)-5-bis-(hydroxymethyl)-3-(tetradecanylidene)-tetrahydro-2-furanone
• 英文别名: (3Z)-5,5-bis(hydroxymethyl)-3-tetradecylideneoxolan-2-one
• CAS: 172843-20-8
• 化学式: C₂₀H₃₆O₄
• 分子量: 340.503
• InChiKey: RMRWVWXSKRJTQM-JXAWBTAJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  24
• 可旋转键数：
  14
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 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：

  (Z)-5-bis-(hydroxymethyl)-3-(tetradecanylidene)-tetrahydro-2-furanone 在 吡啶 、 4-二甲氨基吡啶 、 乙酸酐 作用下， 以 正己烷 、 二氯甲烷 为溶剂， 生成 rac-(Z)-5-(acetyloxymethyl)-5-(hydroxymethyl)-3-(tetradecanylidene)-tetrahydro-2-furanone
  参考文献：
  名称：

  Conformationally constrained diacylglycerol analogues

  摘要：

  构象受限的二酰基甘油类似物，包含这种类似物的药物组合物，以及使用这种类似物作为蛋白激酶C的激动剂和拮抗剂的方法。

  公开号：

  US05874464A1
• 作为产物：
  描述：

  5-bis<<(tert-butyldiphenylsilyl)oxy>methyl>tetrahydro-2-furanone 在 四丁基氟化铵 、 甲基磺酰氯 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 zinc(II) chloride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 为溶剂， 反应 6.25h， 生成 (Z)-5-bis-(hydroxymethyl)-3-(tetradecanylidene)-tetrahydro-2-furanone
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol. 10. Ultrapotent Protein Kinase C Ligands Based on a Racemic 5-Disubstituted Tetrahydro-2-furanone Template

  摘要：

  5,5-Bis(hydroxymethyl)tetrahydro-2-furanone and its isomer 4,4-bis(hydroxymethyl)tetrahydro-2-furanone were investigated as possible templates for the construction of conformationally constrained analogues of the biologically important second messenger, diacylglycerol (DAG). The former lactone contains embedded within its structure an exact glycerol moiety, while in the latter the ring oxygen has been transposed to the other side of the carbonyl group. Al target compounds were synthesized as racemates from 1,3-dihydroxy-2-propanone. The 5,5-bis(hydroxymethyl)tetrahydro-2-furanone proved to be the better template for the construction of DAG surrogates that were demonstrated to have high binding affinities for the biological target, protein kinase C (PK-C). The simplest target compounds derived from this template (3e and 3f) have one of the hydroxyl moieties functionalized either as a myristate or as an oleate ester. The simplest target compound (9e) derived from the ineffective 4,4-bis(hydroxymethyl)tetrahydro-2-furanone template was investigated only with a myristoyl acyl chain. Reducing the long acyl chain to an acetyl moiety and attaching a compensating lipophilic chain to the lactone ring as an alpha-alkylidene moiety produced compounds 10e and 10f(Z-isomers) and 11e and 11f(E-isomers), which were constructed on the more effective 5,5-bis(hydroxymethyl)tetrahydro-2-furanone template. Targets 14c (Z-isomer) and 15c (E-isomer) were derived, in turn, from 4,4-bis(hydroxymethyl)tetrahydro-2-furan. The affinities of these ligands for PK-C were assessed in terms of their ability to displace bound [H-3-20]phorbol 12,13-dibutyrate (PDBU) from the single isozyme PK-C alpha. The biological data support the hypothesis that the increase in binding affinity for PK-C shown by some of these constrained DAG mimetics appears to be entropic in nature. Two of the designed ligands (10e and 10f) showed the highest affinities (34 and 24 nM, respectively) reported so far for a DAG analogue. Assuming that the interaction between these racemic compounds and PK-C is stereospecific, the potency of the active enantiomer is anticipated to double.

  DOI：

  10.1021/jm950276v

文献信息

• Conformationally constrained analogues of diacylglycerol (DAG). 15.1 The indispensable role of the sn-1 and sn-2 carbonyls in the binding of DAG-lactones to protein kinase C (PK-C)
  作者：Samira Benzaria、Bruno Bienfait、Kassoum Nacro、Shaomeng Wang、Nancy E Lewin、Maryam Beheshti、Peter M Blumberg、Victor E Marquez

  DOI：10.1016/s0960-894x(98)00614-3

  日期：1998.12

  The binding mode of DAG-lactones to PK-C was investigated using the C1b domain from the Xray structure of the phorbol ester/C1b complex of PK-C delta as a template. Modeling experiments revealed two binding alternatives in which one of the carbonyls of the DAG lactones remained uninvolved with the protein. Experimentally, however, the removal of either sn-1 or sn-2 carbonyls caused a dramatic drop in binding affinity towards PK-C. Although it was not possible to discriminate between the two binding alternatives of the DAG-lactones, the study demonstrates an important role for the additional carbonyl group. The function of this group could be equivalent to that of the C-9(OH)/C-13 (C=O) motif in phorbol esters, which also appears free of interactions in the phorbol ester/C1b complex. This role presumably reflects interaction with the phosholipid head groups required for high affinity binding under the conditions of the biological assays. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Conformationally constrained diacylglycerol analogues
  申请人：The United States of America as represented by the Department of Health

  公开号：US05874464A1

  公开（公告）日：1999-02-23

  Conformationally constrained diacylglycerol analogues, pharmaceutical compositions comprising such analogues, and methods of using such analogues as agonists and antagonists of protein kinase C.

  构象受限的二酰基甘油类似物，包含这种类似物的药物组合物，以及使用这种类似物作为蛋白激酶C的激动剂和拮抗剂的方法。
• Conformationally Constrained Analogues of Diacylglycerol. 10. Ultrapotent Protein Kinase C Ligands Based on a Racemic 5-Disubstituted Tetrahydro-2-furanone Template
  作者：Rajiv Sharma、Jeewoo Lee、Shaomeng Wang、George W. A. Milne、Nancy E. Lewin、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm950276v

  日期：1996.1.1

  5,5-Bis(hydroxymethyl)tetrahydro-2-furanone and its isomer 4,4-bis(hydroxymethyl)tetrahydro-2-furanone were investigated as possible templates for the construction of conformationally constrained analogues of the biologically important second messenger, diacylglycerol (DAG). The former lactone contains embedded within its structure an exact glycerol moiety, while in the latter the ring oxygen has been transposed to the other side of the carbonyl group. Al target compounds were synthesized as racemates from 1,3-dihydroxy-2-propanone. The 5,5-bis(hydroxymethyl)tetrahydro-2-furanone proved to be the better template for the construction of DAG surrogates that were demonstrated to have high binding affinities for the biological target, protein kinase C (PK-C). The simplest target compounds derived from this template (3e and 3f) have one of the hydroxyl moieties functionalized either as a myristate or as an oleate ester. The simplest target compound (9e) derived from the ineffective 4,4-bis(hydroxymethyl)tetrahydro-2-furanone template was investigated only with a myristoyl acyl chain. Reducing the long acyl chain to an acetyl moiety and attaching a compensating lipophilic chain to the lactone ring as an alpha-alkylidene moiety produced compounds 10e and 10f(Z-isomers) and 11e and 11f(E-isomers), which were constructed on the more effective 5,5-bis(hydroxymethyl)tetrahydro-2-furanone template. Targets 14c (Z-isomer) and 15c (E-isomer) were derived, in turn, from 4,4-bis(hydroxymethyl)tetrahydro-2-furan. The affinities of these ligands for PK-C were assessed in terms of their ability to displace bound [H-3-20]phorbol 12,13-dibutyrate (PDBU) from the single isozyme PK-C alpha. The biological data support the hypothesis that the increase in binding affinity for PK-C shown by some of these constrained DAG mimetics appears to be entropic in nature. Two of the designed ligands (10e and 10f) showed the highest affinities (34 and 24 nM, respectively) reported so far for a DAG analogue. Assuming that the interaction between these racemic compounds and PK-C is stereospecific, the potency of the active enantiomer is anticipated to double.