Garcinoic acid

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: Garcinoic acid
• 英文别名: δ-garcinoic acid；(2E,6E,10E)-13-[(2R)-6-hydroxy-2,8-dimethyl-3,4-dihydrochromen-2-yl]-2,6,10-trimethyltrideca-2,6,10-trienoic acid
• 化学式: C₂₇H₃₈O₄
• 分子量: 426.596
• InChiKey: QOFWRHWADNWKSU-LRXIOGKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 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：

  Garcinoic acid 在 吡啶 、 chromium dichloride 、 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 高氯酸 、 bis(acetylacetonate)oxovanadium 、 SiO₂-supported NaIO₄ 、 N-苯甲酰苯基羟胺 、 碳酸氢钠 、 三乙胺 、 sodium iodide 、 sodium hydroxide 、 nickel dichloride 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 120.25h， 生成 δ-amplexichromanol
  参考文献：
  名称：

  Efficient Semi-Synthesis of Natural δ-(R)-Tocotrienols from a Renewable Vegetal Source

  摘要：

  Recent studies have highlighted the biological potential of tocotrienols, a vitamin E subfamily. The major natural sources of tocotrienols are complex mixtures requiring particularly challenging purification processes. The present study describes efficient semi-synthetic strategies toward relevant.5-(R)-tocotrienol derivatives, using as a starting material 6-(R)-garcinoic acid, the major vitamin E derivative isolated from Garcinia kola nuts, a renewable vegetal source.

  DOI：

  10.1021/acs.jnatprod.8b00517
• 作为产物：
  描述：

  4,6-二溴邻甲酚 在 叔丁基过氧化氢 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 palladium dihydroxide 、 N,N-二甲基甲酰胺 2,6-二甲基吡啶 、 chromium(VI) oxide 、 titanium(IV) isopropylate 、 lithium hydroxide 、 sodium hydroxide 、 potassium phosphate 、 正丁基锂 、 sodium dithionite 、 ammonium cerium(IV) nitrate 、 四甲基乙二胺 、 4 A molecular sieve 、 甲基氢醌 、 四丁基氟化铵 、 水 、 氢气 、 叔丁基锂 、 potassium acetate 、 sodium hydride 、 二异丁基氢化铝 、 potassium carbonate 、 对甲苯磺酸 、 溶剂黄146 、 (+)-Weinsaeure-diethylester 、 三乙胺 、 8-甲氧基-9-硼杂双环[3.3.1]壬烷 、 红铝 、 sodium iodide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 正己烷 、 二氯甲烷 、 乙酸乙酯 、 丙酮 、 甲苯 、 正戊烷 、 苯 为溶剂， 反应 33.91h， 生成 Garcinoic acid
  参考文献：
  名称：

  A Stereocontrolled Synthesis of δ-trans-Tocotrienoloic Acid

  摘要：

  A consise stereoselective total synthesis of a naturally occurring polymerase beta inhibitor, delta-trans-tocotrienoloic acid (2), is described. The key step in the synthesis is an acid-catalyzed cyclodehydration reaction. Additionally, this report corrects a previously reported structural assignment, defines the absolute stereochemistry of 2, and defines key structural requirements for polymerase beta inhibition.

  DOI：

  10.1021/ol051849t

文献信息

• Concise semisynthesis of novel phenazine-vitamin E hybrids via regioselective tocopheryl ortho -quinone formation
  作者：Guillaume Viault、Jean-Jacques Helesbeux、Pascal Richomme、Denis Séraphin

  DOI：10.1016/j.tetlet.2018.05.011

  日期：2018.7

  A regioselective method for the semisynthesis of phenazine derivatives has been disclosed through an efficient IBX mediated ortho-quinone formation from vitamin E derivatives. High chemo- and regio-selectivity was observed during the oxidation step and the corresponding 5,6-ortho-quinones could react with various phenylenediamines. Thus, this methodology proves its interest as a concise semisynthetic

  通过有效的IBX介导的由维生素E衍生物形成邻醌的方法，已经公开了一种用于吩嗪衍生物半合成的区域选择性方法。在氧化步骤中观察到高的化学和区域选择性，并且相应的5，6-邻醌可以与各种苯二胺反应。因此，该方法证明了其作为简明的半合成途径的兴趣，从而可以成功地合成吩嗪-维生素E杂种。
• Efficient ortho-formylation in vitamin E series, application to the semi-synthesis of natural 5- and 7-formyl-δ-tocotrienols revealing an unprecedented 5-bromo-7-formyl exchange
  作者：Khaled Alsabil、Guillaume Viault、Sorphon Suor-Cherer、Jean-Jacques Helesbeux、Joumaa Merza、Vincent Dumontet、Luis Manuel Peña-Rodriguez、Pascal Richomme、Denis Séraphin

  DOI：10.1016/j.tet.2017.10.039

  日期：2017.12

  Semi-synthesis of 5- and 7-formyltocopherols and tocotrienols has been developed by ortho-formylation of C-5 or C-7-unsubstituted vitamin E derivatives (14 examples) up to 90% yield, through heating in the presence of respectively 10-10-15 equivalents of MgCl2-Et3N-(CH2O)n. Formylation of 5-bromo-δ-tocotrienol revealed an unprecedented 5-bromo/7-formyl exchange and yielded 7-bromo-5-formyl-δ-tocotrienol

  通过分别在10到10的条件下加热将C-5或C-7-未取代的维生素E衍生物（14个实例）进行邻甲酰化，开发了5-和7-甲酰基生育酚和生育三烯酚的半合成方法。-10-15当量的MgCl 2 -Et 3 N-（CH 2 O）n。5-溴-δ-生育三烯酚的甲酰化显示出前所未有的5-溴/ 7-甲酰基交换，并产生了7-溴-5-甲酰基-δ-生育三烯酚作为主要产物。次要的5-溴-7-甲酰基-δ-生育三烯酚通过三个步骤导致先前从藤黄的茎皮中分离出的7-甲酰基-δ-生育三烯酚。
• Semisynthetic Vitamin E Derivatives as Potent Antibacterial Agents against Resistant Gram‐Positive Pathogens
  作者：Guillaume Viault、Marie Kempf、Alexia Ville、Khaled Alsabil、Rodolphe Perrot、Pascal Richomme、Jean‐Jacques Hélesbeux、Denis Séraphin

  DOI：10.1002/cmdc.202000792

  日期：2021.3.3

  New 5‐substituted vitamin E derivatives were semisynthesized, and their antibacterial activity against human Gram‐positive and Gram‐negative pathogens was evaluated. Several vitamin E analogues were active against methicillin‐resistant Staphylococcus aureus (MRSA) and/or methicillin‐resistant Staphylococcus epidermidis (MRSE); structure‐activity relationships (SARs) are discussed. As a result, it is

  半合成了新的 5 取代维生素 E 衍生物，并评估了它们对人类革兰氏阳性和革兰氏阴性病原体的抗菌活性。几种维生素 E 类似物对耐甲氧西林金黄色葡萄球菌(MRSA) 和/或耐甲氧西林表皮葡萄球菌有活性(MRSE); 讨论了构效关系（SAR）。结果表明，C-5 位和/或侧链末端的羧酸官能团的存在对抗菌活性至关重要。时间-杀伤动力学研究证实了三种化合物对 MRSA 和 MRSE 的杀菌或抑菌作用，并评估了对人体细胞的细胞毒性。共聚焦显微镜的初步机制研究表明，这些维生素 E 类似物通过膜破坏导致细菌细胞死亡。
• Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors
  作者：Chau Phi Dinh、Alexia Ville、Konstantin Neukirch、Guillaume Viault、Veronika Temml、Andreas Koeberle、Oliver Werz、Daniela Schuster、Hermann Stuppner、Pascal Richomme、Jean-Jacques Helesbeux、Denis Séraphin

  DOI：10.1016/j.ejmech.2020.112518

  日期：2020.9

  Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. delta-Garcinoic acid (delta-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. (C) 2020 Elsevier Masson SAS. All rights reserved.
• Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor
  作者：Desirée Bartolini、Francesca De Franco、Pierangelo Torquato、Rita Marinelli、Bruno Cerra、Riccardo Ronchetti、Arne Schon、Francesca Fallarino、Antonella De Luca、Guido Bellezza、Ivana Ferri、Angelo Sidoni、William G. Walton、Samuel J. Pellock、Matthew R. Redinbo、Sridhar Mani、Roberto Pellicciari、Antimo Gioiello、Francesco Galli

  DOI：10.1021/acs.jmedchem.0c00012

  日期：2020.4.9

  Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.