(E)-6-(4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid | 1451181-22-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: (E)-6-(4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid
• 英文别名: (4E)-6-(4-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid；4'-tert-Butyldimethylsilylmycophenolic Acid；(E)-6-[4-[tert-butyl(dimethyl)silyl]oxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl]-4-methylhex-4-enoic acid
• CAS: 1451181-22-8
• 化学式: C₂₃H₃₄O₆Si
• 分子量: 434.605
• InChiKey: ZMTFSZLFEGAGIR-NTEUORMPSA-N

物化性质

• 沸点：
  574.9±50.0 °C(Predicted)
• 密度：
  1.108±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.41
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  82.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (E)-6-(4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid 在 sodium tetrahydroborate 、 四丁基氟化铵 、 sodium methylate 、 二异丁基氢化铝 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 生成 7-hydroxy-5-methoxy-4-methyl-6-[(E)-3-methyl-6-sulfanylhex-2-enyl]-3H-2-benzofuran-1-one
  参考文献：
  名称：

  Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH

  摘要：

  Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5-triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type land II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10 mu M. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.07.016
• 作为产物：
  描述：

  霉酚酸 在 咪唑 、 溶剂黄146 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (E)-6-(4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid
  参考文献：
  名称：

  霉酚酸和a啶/ ac啶酮作为潜在免疫抑制剂的酯衍生物的合成及其生物学活性。

  摘要：

  麦考酚酸（MPA）的改良衍生物对于减少这种药物在治疗患者中产生的不良反应的发生率是必不可少的。在这项研究中，MPA与N-（ω-羟烷基）-9-ac啶酮-4-羧酰胺或N-（ω-羟烷基）ac啶-4-羧酰胺偶联后，根据Yamaguchi方案生成相应的酯共轭物。这种酯化作用需要保护MPA中的酚基。设计的结合物显示出比母体MPA更高的体外效价。cr啶衍生物比a啶酮类似物更具活性，MPA和杂环单元之间的烷基接头长度会影响所观察到的细胞毒性。衍生物2b，2d，3a，3b显示出最有希望的免疫抑制活性。

  DOI：

  10.3109/14756366.2015.1077821

文献信息

• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。
• [EN] LIPID CONJUGATE PREPARED FROM SCAFFOLD MOIETY<br/>[FR] CONJUGUÉ LIPIDIQUE PRÉPARÉ À PARTIR D'UN FRAGMENT SQUELETTE
  申请人：INTEGRATED NANOTHERAPEUTICS INC

  公开号：WO2020191477A1

  公开（公告）日：2020-10-01

  The application relates to a lipid conjugate of formula M-X1-L wherein M is a molecule of interest such as a drug moiety; X1 is a linker group such as ester, ether or carbamate; and L is a lipid scaffold represented by formula (lId): -L1-[L2(H)(X2R)]n-L3-[L4(H)(X2R)]p-L5-L6 and wherein L comprises 5 to 40 carbon atoms and 0 to 2 carbon-carbon double bonds. The lipid conjugate can be formulated in a drug delivery vehicle such as a lipid nanoparticle (LNP).

  该应用涉及公式M-X1-L的脂质共轭物，其中M是感兴趣的分子，如药物基团；X1是连接基团，如酯、醚或氨基甲酸酯；L是由公式(lId)表示的脂质支架：-L1-[L2(H)(X2R)]n-L3-[L4(H)(X2R)]p-L5-L6，其中L包含5至40个碳原子和0至2个碳-碳双键。该脂质共轭物可以配制在药物传递载体中，如脂质纳米粒子（LNP）。
• NHC–BIAN–Cu(I)-Catalyzed Friedländer-Type Annulation of 2-Amino-3-(per)fluoroacetylpyridines with Alkynes on Water
  作者：Magdalena Dolna、Michał Nowacki、Oksana Danylyuk、Artur Brotons-Rufes、Albert Poater、Michał Michalak

  DOI：10.1021/acs.joc.2c00380

  日期：2022.5.6

  The direct catalytic alkynylation/dehydrative cyclization of 2-amino-3-trifluoroacetyl-pyridines on water was developed for the efficient synthesis of a broad range of fluorinated 1,8-naphthyridines from terminal alkynes. A novel N-heterocyclic carbene (NHC) ligand system that combines a π-extended acenaphthylene backbone with sterically bulky pentiptycene pendant groups was successfully utilized in

  开发了 2-氨基-3-三氟乙酰基吡啶在水中的直接催化炔基化/脱水环化，用于从末端炔烃高效合成广泛的氟化 1,8-萘啶。一种新的 N-杂环卡宾 (NHC) 配体系统将 π 延伸的苊主链与空间庞大的戊二烯侧基相结合，成功地用于铜或银介导的环化。反应路径的计算分析支持我们对一组铜和银催化剂的不同实验转化率和产率的解释。还讨论了金属中心的空间位阻和NHC咪唑环上取代基的柔韧性对催化性能的影响。
• Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH
  作者：Kazuhiro Sunohara、Shinya Mitsuhashi、Kengo Shigetomi、Makoto Ubukata

  DOI：10.1016/j.bmcl.2013.07.016

  日期：2013.9

  Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5-triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type land II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10 mu M. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC. (C) 2013 Elsevier Ltd. All rights reserved.
• Synthesis and biological activity of ester derivatives of mycophenolic acid and acridines/acridones as potential immunosuppressive agents
  作者：Grzegorz Cholewinski、Dorota Iwaszkiewicz-Grzes、Piotr Trzonkowski、Krystyna Dzierzbicka

  DOI：10.3109/14756366.2015.1077821

  日期：2016.11.1

  Improved derivatives of mycophenolic acid (MPA) are necessary to reduce the frequency of adverse effects, this drug exerts in treated patients. In this study, MPA was coupled with N-(ω-hydroxyalkyl)-9-acridone-4-carboxamides or N-(ω-hydroxyalkyl)acridine-4-carboxamides to give respective ester conjugates upon Yamaguchi protocol. This esterification required protection of phenol group in MPA. Designed

  麦考酚酸（MPA）的改良衍生物对于减少这种药物在治疗患者中产生的不良反应的发生率是必不可少的。在这项研究中，MPA与N-（ω-羟烷基）-9-ac啶酮-4-羧酰胺或N-（ω-羟烷基）ac啶-4-羧酰胺偶联后，根据Yamaguchi方案生成相应的酯共轭物。这种酯化作用需要保护MPA中的酚基。设计的结合物显示出比母体MPA更高的体外效价。cr啶衍生物比a啶酮类似物更具活性，MPA和杂环单元之间的烷基接头长度会影响所观察到的细胞毒性。衍生物2b，2d，3a，3b显示出最有希望的免疫抑制活性。