(E)-5-(hydroxymethyl)-3-[5-methyl-3-(2-methylpropyl)hexylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one | 497819-05-3

• 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: (E)-5-(hydroxymethyl)-3-[5-methyl-3-(2-methylpropyl)hexylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one
• 英文别名: E-5-(hydroxymethyl)-3-[5-methyl-3-(2-methylpropyl)hexylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one；(E)-5-((benzyloxy)methyl)-5-(hydroxymethyl)-3-(3-isobutyl-5-methylhexylidene)dihydrofuran-2(3H)-one；(E)-5-(benzyloxymethyl)-5-(hydroxymethyl)-3-(3-isobutyl-5-methylhexylidene)dihydrofuran-2(3H)-one
• CAS: 497819-05-3
• 化学式: C₂₄H₃₆O₄
• 分子量: 388.547
• InChiKey: YGQGVGZFXKLIKS-SSDVNMTOSA-N

物化性质

• 沸点：
  518.6±35.0 °C(Predicted)
• 密度：
  1.065±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.91
• 重原子数：
  28.0
• 可旋转键数：
  11.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  55.76
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (E)-5-(hydroxymethyl)-3-[5-methyl-3-(2-methylpropyl)hexylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one 在 4-二甲氨基吡啶 三氯化硼 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.17h， 生成 E-{2-(hydroxymethyl)-4-[5-methyl-3-(2-methylpropyl)hexylidene]-5-oxo-2-(2,3-dihydrofuryl)}methyl 3-methylbutanoate
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol (DAG). 28. DAG-dioxolanones Reveal a New Additional Interaction Site in the C1b Domain of PKCδ

  摘要：

  Diacylglycerol (DAG) lactones have provided a powerful platform for structural exploration of the interactions between ligands and the C1 domains of protein kinase C (PKC). In this study, we report that DAG-dioxolanones, novel derivatives of DAG-lactones, exploit an additional point of contact (glutamine 27) in their binding with the C1b domain of PKC delta. Mutation of this point of contact to glutamate selectively impairs binding of the DAG-dioxolanones compared to that of the corresponding DAG-lactones (1200- to 3000-fold versus 35- to 55-fold, respectively). The differential response of this mutated C1b domain to the DAG-dioxolanones relative to the DAG-lactones provides a unique tool to probe the role of the C1b domain in PKC delta function, where the response to the DAG-lactones affords a positive control for retained function. Using this approach, we show that the C1b domain of PKC delta plays the predominant role in the translocation of PKC delta to the membrane in the presence of DAG.

  DOI：

  10.1021/jm0702579
• 作为产物：
  描述：

  1-(benzyloxy)-2-[(4-methoxyphenoxy)methyl]-4-penten-2-ol 在 ammonium cerium(IV) nitrate 、 dimethyl sulfide borane 、 甲基磺酰氯 、 三乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 0.75h， 生成 (E)-5-(hydroxymethyl)-3-[5-methyl-3-(2-methylpropyl)hexylidene]-5-[(phenylmethoxy)methyl]-4,5-dihydrofuran-2-one
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol (DAG). 28. DAG-dioxolanones Reveal a New Additional Interaction Site in the C1b Domain of PKCδ

  摘要：

  Diacylglycerol (DAG) lactones have provided a powerful platform for structural exploration of the interactions between ligands and the C1 domains of protein kinase C (PKC). In this study, we report that DAG-dioxolanones, novel derivatives of DAG-lactones, exploit an additional point of contact (glutamine 27) in their binding with the C1b domain of PKC delta. Mutation of this point of contact to glutamate selectively impairs binding of the DAG-dioxolanones compared to that of the corresponding DAG-lactones (1200- to 3000-fold versus 35- to 55-fold, respectively). The differential response of this mutated C1b domain to the DAG-dioxolanones relative to the DAG-lactones provides a unique tool to probe the role of the C1b domain in PKC delta function, where the response to the DAG-lactones affords a positive control for retained function. Using this approach, we show that the C1b domain of PKC delta plays the predominant role in the translocation of PKC delta to the membrane in the presence of DAG.

  DOI：

  10.1021/jm0702579

文献信息

• Design, Synthesis, and Characterization of Novel <i>sn</i>-1 Heterocyclic DAG-Lactones as PKC Activators
  作者：Eleonora Elhalem、Ana Bellomo、Mariana Cooke、Antonella Scravaglieri、Larry V. Pearce、Megan L. Peach、Lucía Gandolfi Donadío、Marcelo G. Kazanietz、María J. Comin

  DOI：10.1021/acs.jmedchem.1c00739

  日期：2021.8.12

  PKC isozymes. The ester moiety at the sn-1 position, a common feature in this template, is relevant for C1 domain interactions, but it represents a labile group susceptible to endogenous esterases. An interesting challenge involves replacing the ester group of these ligands while still maintaining biological activity. Here, we present the synthesis and functional characterization of novel diacylglycerol-lactones

  DAG-内酯代表了用于设计 PKC 同工酶的有效和选择性 C1 域配体的有用模板。sn -1 位置的酯部分是该模板中的一个共同特征，与 C1 域相互作用相关，但它代表易受内源性酯酶影响的不稳定基团。一个有趣的挑战涉及替换这些配体的酯基，同时仍保持生物活性。在这里，我们介绍了在sn -1 位置含有杂环取代基的新型二酰基甘油-内酯的合成和功能表征。我们的结果表明，新化合物10B12是一种具有异恶唑环的DAG-内酯，以纳摩尔亲和力结合 PKCα 和 PKCε。值得注意的是，10B12在细胞中对 PKCε 易位显示优先选择性，并诱导 PKCε 依赖性肌动蛋白细胞骨架重组为肺癌细胞的外周褶皱。我们得出结论，在 DAG-内酯中引入稳定的异恶唑环作为酯替代物是一种实现 PKC 同工酶选择性的新型结构方法。
• Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKCα, PKCε, and RasGRP
  作者：Eleonora Elhalem、Lucía Gandolfi Donadío、Xiaoling Zhou、Nancy E. Lewin、Lia C. Garcia、Christopher C. Lai、James A. Kelley、Megan L. Peach、Peter M. Blumberg、María J. Comin

  DOI：10.1016/j.bmc.2017.03.022

  日期：2017.6

  Cl domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins. One current challenge is the development of selective ligands capable of discriminating between different protein family members. Recently, structure-activity relationship studies have shown that the introduction of an indole ring as a DAG-lactone substituent yielded selective Ras guanine nucleotide-releasing protein (RasGRP1) activators when compared to PKC alpha and PKC epsilon. In the present work, we examine the effects of ligand selectivity relative to the orientation of the indole ring and the nature of the DAG-lactone template itself. Our results show that the indole ring must be attached to the lactone moiety through the sn-2 position in order to achieve Ra5GRP1 selectivity. (C) 2017 Elsevier Ltd. All rights reserved.
• Diacylglycerol Lactones Targeting the Structural Features That Distinguish the Atypical C1 Domains of Protein Kinase C ζ and ι from Typical C1 Domains
  作者：Yongmei Pu、Ji-Hye Kang、Dina M. Sigano、Megan L. Peach、Nancy E. Lewin、Victor E. Marquez、Peter M. Blumberg

  DOI：10.1021/jm500165n

  日期：2014.5.8

  To explore the feasibility of developing ligands targeted to the atypical C1 domains of protein kinase C zeta and iota, we have prepared diacylglycerol lactones substituted with hydrophilic groups on their side chains, which potentially could interact with the arginine residues that distinguish the atypical C1 domains of PKC zeta and PKC?iota from typical C1 domains, and we have measured their binding to mutated versions of the C1b domain of PKC delta that incorporate one or more of these arginine residues. The most selective of the diacylglycerol lactones showed only a 10-fold reduction in binding affinity with the triple arginine mutant (N7R/S10R/L20R) compared to the wild-type, whereas phorbol 12,13-dibutyrate showed a 6000-fold loss of affinity. Molecular modeling confirms that these ligands are indeed able to interact with the arginine residues. Our results show that dramatic changes in selectivity can be obtained through appropriate substitution of diacylglycerol lactones.
• Conformationally Constrained Analogues of Diacylglycerol. 19. Synthesis and Protein Kinase C Binding Affinity of Diacylglycerol Lactones Bearing an <i>N</i>-Hydroxylamide Side Chain
  作者：Yongseok Choi、Ji-Hye Kang、Nancy E. Lewin、Peter M. Blumberg、Jeewoo Lee、Victor E. Marquez

  DOI：10.1021/jm030082c

  日期：2003.6.1

  The structures of N-hydroxylamides 1a and 1b, previously reported by Lee et al. in J. Med. Chem. 2001, 44, 4309-4312 as strong protein kinase C (PK-C) ligands, were incorrect and correspond instead to esters 2a and 2b, respectively. Here, we report the synthesis and complete characterization of 1a and 1b together with the associated biological activity in terms of PK-C binding affinity.