4-(羟基甲基)苯基丙酸酯 | 773873-35-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚酯
• 中文名称: 4-(羟基甲基)苯基丙酸酯
• 中文别名: 吡啶并[1,2-a]苯并咪唑，2-甲基-(9CI)
• 英文名称: 4-(hydroxymethyl)phenyl propionate
• 英文别名: 4-(Hydroxymethyl)phenyl propanoate；[4-(hydroxymethyl)phenyl] propanoate
• CAS: 773873-35-1
• 化学式: C₁₀H₁₂O₃
• mdl: MFCD06203117
• 分子量: 180.203
• InChiKey: VXDNHROQIGVQIR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  13
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 海关编码：
  2915509000

反应信息

• 作为反应物：
  描述：

  4-(羟基甲基)苯基丙酸酯 在 吡啶 、 N-氯代丁二酰亚胺 、 亚磷酸二苯酯 、 三乙胺 、 三氟乙酸酐 作用下， 以 乙腈 为溶剂， 反应 6.84h， 生成
  参考文献：
  名称：

  γ-烷基修饰的三磷酸核苷的前药可改善对HIV逆转录酶的抑制作用。

  摘要：

  核苷三磷酸前药的开发是应用核苷逆转录酶抑制剂的一种选择。本文中，我们报告了d4TTP类似物的合成和评估，其中γ-磷酸被亲脂性烷基残基和这些γ-烷基修饰的d4TTP的酰氧基苄基前药共价修饰，目的是将γ-烷基-d4TTP引入细胞。用酯酶和CD4 +证明了γ-烷基-d4TTP的选择性形成细胞提取物。与d4TTP相比，γ-烷基-d4TTP表现出高度的去磷酸化稳定性。用HIV逆转录酶（RT）和DNA聚合酶α，β或γ进行的引物延伸分析表明，γ-烷基-d4TTP仅是HIV-RT的底物。在抗病毒测定，化合物在胸苷激酶缺陷型T细胞培养物（CEM / TK HIV-1和HIV-2也高度有效的抑制剂- ）。因此，此类γ-烷基-核苷三磷酸的细胞内传递可能会导致对可在病毒感染的细胞中起作用的病毒聚合酶具有更高选择性的核苷三磷酸。

  DOI：

  10.1002/anie.202003073
• 作为产物：
  描述：

  对羟基苯甲醛 在 sodium tetrahydroborate 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 4-(羟基甲基)苯基丙酸酯
  参考文献：
  名称：

  Formulating a new basis for the treatment against botulinum neurotoxin intoxication: 3,4-Diaminopyridine prodrug design and characterization

  摘要：

  Botulism is a disease characterized by neuromuscular paralysis and is produced from botulinum neurotoxins (BoNTs) found within the Gram positive bacterium Clostridium botulinum. This bacteria produces the most deadliest toxin known, with lethal doses as low as 1 ng/kg. Due to the relative ease of production and transport, the use of these agents as potential bioterrorist weapons has become of utmost concern. No small molecule therapies against BoNT intoxication have been approved to date. However, 3,4-diaminopyridine (3,4-DAP), a potent reversible inhibitor of voltage-gated potassium channels, is an effective cholinergic agonist used in the treatment of neuromuscular degenerative disorders that require cholinergic enhancement. 3,4-DAP has also been shown to facilitate recovery of neuromuscular action potential post botulinum intoxication by blocking K(+) channels. Unfortunately, 3,4-DAP displays toxicity largely due to blood-brain-barrier (BBB) penetration. As a dual-action prodrug approach to cholinergic enhancement we have designed carbamate and amide conjugates of 3,4-DAP. The carbamate prodrug is intended to be a slowly reversible inhibitor of acetylcholinesterase (AChE) along the lines of the stigmines thereby allowing increased persistence of released acetylcholine within the synaptic cleft. As a secondary activity, cleavage of the carbamate prodrug by AChE will afford the localized release of 3,4-DAP, which in turn, will enhance the pre-synaptic release of additional acetylcholine. Being a competitive inhibitor with respect to acetylcholine, the activity of the prodrug will be greatest at the synaptic junctions most depleted of acetylcholine. Here we report upon the synthesis and biochemical characterization of three new classes of prodrugs intended to limit previously reported stability and toxicity issues. Of the prodrugs examined, compound 32, demonstrated the most clinically relevant half-life of 2.76 h, while selectively inhibiting AChE over butyrylcholinesterase-a plasma-based high activity esterase. Future in vivo studies could provide validation of prodrug 32 as a potential treatment against BoNT intoxication as well as other neuromuscular disorders. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.09.019

文献信息

• γ‐Non‐Symmetrically Dimasked Tri <i>PPP</i> ro Prodrugs as Potential Antiviral Agents against HIV
  作者：Chenglong Zhao、Xiao Jia、Dominique Schols、Jan Balzarini、Chris Meier

  DOI：10.1002/cmdc.202000712

  日期：2021.2.4

  Nucleoside analogue reverse transcriptase inhibitors (NRTI) and nucleoside analogue monophosphate prodrugs are used in combination antiretroviral therapy (cART). The design of antivirally active nucleoside triphosphate prodrugs is a recent and an important advancement in the field of nucleoside analogue drug development. Here, we report on TriPPPro‐derivatives of nucleoside analogue triphosphates (NTPs)

  核苷类似物逆转录酶抑制剂 (NRTI) 和核苷类似物单磷酸酯前药用于联合抗逆转录病毒疗法 (cART)。具有抗病毒活性的三磷酸核苷前药的设计是核苷类似物药物开发领域的一项重要进展。在这里，我们报告了核苷类似物三磷酸 (NTPs) 的Tri PPP ro-derivatives，在 NTP 的 γ-磷酸处包含两个不同的酰氧基苄基掩码，旨在实现代谢旁路。因此，合成了 γ-非对称双掩蔽的 Tri PPP ro-化合物（γ-（AB，ab）-d4TTPs），并证明它们在感染的野生型人类 CD4 +培养物中对 HIV-1 和 HIV-2 具有活性T 淋巴细胞 (CEM/0) 细胞，更重要的是胸苷激酶缺陷型 CD4 + T 细胞 (CEM/TK-)。在磷酸盐缓冲液（PB，pH 7.3）和 CEM 细胞提取物中的水解研究中，令人惊讶的是，两种酰氧基苄基前药掩膜的裂解没有差异。然而，如果在两个酰氧基苄基之一中引入了一个短的
• Anti-HIV-Active Nucleoside Triphosphate Prodrugs
  作者：Xiao Jia、Dominique Schols、Chris Meier

  DOI：10.1021/acs.jmedchem.0c00271

  日期：2020.6.11

  We disclose a study on nucleoside triphosphate (NTP) analogues in which the γ-phosphate is covalently modified by two different biodegradable masking units and d4T as nucleoside analogue that enable the delivery of d4TTP with high selectivity in phosphate buffer (pH 7.3) and by enzyme-triggered reactions in human CD4+ T-lymphocyte CEM cell extracts. This allows the bypass of all steps normally needed

  我们公开了一项关于核苷三磷酸酯（NTP）类似物的研究，其中γ-磷酸酯被两个不同的可生物降解的掩蔽单元和d4T进行了共价修饰，从而使d4TTP在磷酸盐缓冲液（pH 7.3）和酶中具有较高的选择性CD4 + T淋巴细胞CEM细胞提取物中触发的反应。这允许绕过细胞内磷酸化通常所需的所有步骤。这些Tri PPP将包含酰氧基苄基（AB；酯）或烷氧基羰氧基苄基（ACB；碳酸酯）与ACB部分结合的环核苷酸描述为NTP递送系统。这两个不同基团的引入导致通过化学水解，特别是通过细胞提取酶选择性地形成γ-（ACB）-d4TTP。γ-（AB）-d4TTP的裂解速度比γ-（ACB）-d4TTP更快。在抗病毒测定中，这些化合物在野生型CEM / O细胞中具有更强的抗HIV-1和HIV-2活性，更重要的是在缺乏胸苷激酶的CD4 + T细胞（CEM / TK –）中具有很高的活性。
• METHOD FOR SYNTHESIZING PEPTIDES IN CELL-FREE TRANSLATION SYSTEM
  申请人：Chugai Seiyaku Kabushiki Kaisha

  公开号：US20200040372A1

  公开（公告）日：2020-02-06

  An objective of the present invention is to provide methods of synthesizing peptides containing structurally diverse amino acids using cell-free translation systems, which can accomplish excellent translational efficiency as compared to conventional techniques (the conventional techniques being methods which involve preparing aminoacyl-tRNAs which do not have protecting groups outside the translation systems without using ARS, and then adding the prepared aminoacyl-tRNAs into translation systems). In the present invention, it was found that amino acid-containing peptides can be synthesized efficiently by protecting an amino acid linked to tRNA with an appropriate protecting group, and then performing the step of deprotecting the protecting group of the amino acid linked to tRNA and the step of peptide translation from a template nucleic acid in a cell-free translation system in parallel.

  本发明的一个目标是提供使用无细胞翻译系统合成含有结构多样的氨基酸的肽的方法，这些方法可以实现与传统技术相比出色的翻译效率（传统技术是指涉及在翻译系统外部准备没有保护基的氨酰-tRNA而不使用ARS的方法，然后将准备好的氨酰-tRNA添加到翻译系统中）。在本发明中，发现通过用适当的保护基保护与tRNA连接的氨基酸，然后并行进行去保护氨基酸与tRNA连接的保护基的步骤和从模板核酸进行肽翻译的步骤，可以高效地合成含有氨基酸的肽。
• Lipophilic Triphosphate Prodrugs of Various Nucleoside Analogues
  作者：Xiao Jia、Dominique Schols、Chris Meier

  DOI：10.1021/acs.jmedchem.0c00358

  日期：2020.7.9

  The antiviral efficacy of many nucleoside analogues is strongly dependent on their intracellular activation by host cellular kinases to yield ultimately the bioactive nucleoside analogue triphosphates (NTP). The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. We developed a nucleoside triphosphate (NTP) delivery system (the TriPPPro approach), in

  许多核苷类似物的抗病毒功效在很大程度上取决于宿主细胞激酶对它们的胞内活化作用，从而最终产生具有生物活性的核苷类似物三磷酸酯（NTP）。核苷类似物代谢转化为三磷酸酯的过程通常进行得不充分。我们开发了三磷酸核苷（NTP）递送系统（Tri PPPRO法），其中γ-磷酸盐被两个不同的可生物降解的掩蔽单元共价修饰，一个是酰氧基苄基（AB）部分，另一个是烷氧基羰氧基苄基（ACB）基团。这样的化合物通过酶触发的机制在人T淋巴细胞CEM细胞提取物中形成高选择性的NTP，首先失去AB部分，然后失去ACB基团。这使得能够绕过细胞内磷酸化的所有步骤。在此应用此方法将某些中等活性或什至无活性的核苷类似物转化为强大的生物活性代谢物。根据在感染的野生型CD4 +的培养物中针对HIV-1和HIV-2复制的Tri PPP ro-NTP前药的亲脂性，可以获得有效的抗病毒活性。CEM T细胞，更重要的是在缺乏胸苷激酶的CD4
• γ-Ketobenzyl-Modified Nucleoside Triphosphate Prodrugs as Potential Antivirals
  作者：Tobias Nack、Thiago Dinis de Oliveira、Stefan Weber、Dominique Schols、Jan Balzarini、Chris Meier

  DOI：10.1021/acs.jmedchem.0c01293

  日期：2020.11.25

  The antiviral activity of nucleoside reverse transcriptase inhibitors is often hampered by insufficient phosphorylation. Nucleoside triphosphate analogues are presented, in which the γ-phosphate was covalently modified by a non-bioreversible, lipophilic 4-alkylketobenzyl moiety. Interestingly, primer extension assays using human immunodeficiency virus reverse transcriptase (HIV-RT) and three DNA-polymerases

  核苷逆转录酶抑制剂的抗病毒活性通常受到磷酸化不足的阻碍。提出了核苷三磷酸酯类似物，其中γ-磷酸酯被非生物可逆的亲脂性4-烷基酮苄基部分共价修饰。有趣的是，使用人类免疫缺陷病毒逆转录酶（HIV-RT）和三种DNA聚合酶进行引物延伸分析显示，这些γ-修饰的核苷三磷酸作为HIV-RT的底物具有很高的选择性，而事实证明它们不是DNA-的非底物。聚合酶α，β和γ。与d4TTP相比，γ-修饰的d4TTP在细胞提取物中表现出对去磷酸化的高抗性。制备了这些γ-酮苄基核苷三磷酸的一系列酰氧基苄基前药。目的是在细胞内递送稳定的γ-修饰的三磷酸核苷，以增加此类化合物在感染细胞与未感染细胞中起作用的选择性。γ-酮苄基-d4TTP的传递已在T淋巴细胞细胞提取物中得到证实。在感染的CEM / 0细胞培养物中，前药是有效的HIV-1 / 2抑制剂，更重要的是在胸苷激酶缺陷型CD4中+ T细胞。