3-isobutyl-5-methylhexanal | 388621-92-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-isobutyl-5-methylhexanal
• 英文别名: 5-methyl-3-(2-methylpropyl)hexan-1-one；Hexanal, 5-methyl-3-(2-methylpropyl)-；5-methyl-3-(2-methylpropyl)hexanal
• CAS: 388621-92-9
• 化学式: C₁₁H₂₂O
• 分子量: 170.295
• InChiKey: SGDDLQCALMFFSA-UHFFFAOYSA-N

物化性质

• 沸点：
  211.9±8.0 °C(Predicted)
• 密度：
  0.816±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  12
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  17.1
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  3-isobutyl-5-methylhexanal 在 4-二甲氨基吡啶 ammonium cerium(IV) nitrate 、 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 0.92h， 生成 Z-{4-[5-methyl-3-(2-methylpropyl)hexylidene]-5-oxo-2-[(phenylmethoxy)methyl]-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：

  二异丁基酮 在 palladium on activated charcoal 4 A molecular sieve 、 氢气 、 pyridinium chlorochromate 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 27.0h， 生成 3-isobutyl-5-methylhexanal
  参考文献：
  名称：

  Conformationally Constrained Analogues of Diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 Carbonyl Functionality Reveals the Essential Role of the sn-1 Carbonyl at the Lipid Interface in the Binding of DAG-Lactones to Protein Kinase C

  摘要：

  Diacylglycerol (DAG) lactones with altered functionality (C=O -> CH2 or C=O -> C=S) at the sn-1 and sn-2 carbonyl pharmacophores were synthesized and used as probes to dissect the individual role of each carbonyl in the binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen-bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (Cl domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to ensure the correct orientation and disposition of pharmacophores at the binding site.

  DOI：

  10.1021/jm050352m

文献信息

• [EN] PROTEIN KINASE C AGONISTS<br/>[FR] AGONISTES DE PROTÉINE KINASE C
  申请人：GILEAD SCIENCES INC

  公开号：WO2020176505A1

  公开（公告）日：2020-09-03

  The present disclosure relates generally to certain diacylglycerol lactone compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by protein kinase C (PKC) agonists, such as HIV.

  本公开涉及某些二酰基甘油内酯化合物，包括该化合物的药物组合物，以及制备和使用该化合物和药物组合物的方法。本文所披露的化合物和组合物可用于治疗或预防可通过蛋白激酶C（PKC）激动剂调节的疾病、疾病或感染，如艾滋病。
• Conformationally Constrained Analogues of Diacylglycerol. 18. The Incorporation of a Hydroxamate Moiety into Diacylglycerol-Lactones Reduces Lipophilicity and Helps Discriminate between <i>sn-1</i> and <i>sn-2</i> Binding Modes to Protein Kinase C (PK-C). Implications for Isozyme Specificity
  作者：Jeewoo Lee、Kee-Chung Han、Ji-Hye Kang、Larry L. Pearce、Nancy E. Lewin、Shunqi Yan、Samira Benzaria、Marc C. Nicklaus、Peter M. Blumberg、Victor E. Marquez

  DOI：10.1021/jm0103965

  日期：2001.12.1

  approach to reduce the log P in a series of diacylglycerol (DAG)-lactones known for their high binding affinity for protein kinase C (PK-C) is presented. Branched alkyl groups with reduced lipophilicity were selected and combined with the replacement of the ester or lactone oxygens by NH or NOH groups. Compound 6a with an isosteric N-hydroxyl amide arm represents the most potent and least lipophilic DAG analogue

  提出了一种减少一系列二酰基甘油（DAG）-内酯中的log P的方法，这些内酯对蛋白激酶C（PK-C）具有高结合亲和力。选择具有降低的亲脂性的支链烷基，并结合用NH或NOH基团取代酯或内酯氧。具有等排N-羟基酰胺基臂的化合物6a代表迄今为止已知的最有效和最不亲脂的DAG类似物。
• Conformationally Constrained Analogues of Diacylglycerol. 24. Asymmetric Synthesis of a Chiral (<i>R</i>)-DAG-Lactone Template as a Versatile Precursor for Highly Functionalized DAG-Lactones
  作者：Ji-Hye Kang、Maqbool A. Siddiqui、Dina M. Sigano、Krzysztof Krajewski、Nancy E. Lewin、Yongmei Pu、Peter M. Blumberg、Jeewoo Lee、Victor E. Marquez

  DOI：10.1021/ol0492041

  日期：2004.7.1

  2-methylenepropane-1,3-diol was converted to chiral epoxide (R)-2 via Sharpless asymmetric epoxidation in >96% ee. Regiospecific epoxide ring opening and reduction of the intermediate alkyne set the stage for a one-pot lactonization to give (R)-6, a convenient precursor for all functionalized chiral DAG-lactones used as potent PK-C ligands. The synthesis of the most potent DAG-lactones known to date

  [结构：见正文]通过> 96％ee的Sharpless不对称环氧化，将市售的2-亚甲基丙烷-1,3-二醇转化为手性环氧化物（R）-2。区域特异性环氧化物的开环和中间炔烃的还原为单锅内酯化提供了条件，以得到（R）-6，这是用作功能强大的PK-C配体的所有官能化手性DAG内酯的便利前体。迄今为止已知的最有效的DAG内酯（Z）-10和（E）-10的合成，证实了PK-C在此类化合物中对（R）-立体化学的排他性偏好。
• 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.