4-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid | 1135117-94-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
• CAS: 1135117-94-0
• 化学式: C₁₅H₉FN₂O₃
• 分子量: 284.246
• InChiKey: BETRRDBSHACORV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  76.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid 在 草酰氯 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  级联 C-H 活化/氧化亚叶立德与乙烯基环丙烷的环化：获得环丙烷稠合的 α-四氢萘酮

  摘要：

  Rh 催化的弱和无痕定向基团辅助级联 C-H 活化和氧化亚叶立德与乙烯基环丙烷作为偶联伙伴的环化已经完成，以在中等温度下提供功能化的环丙烷稠合四氢萘酮。C-C键形成、环丙烷化、官能团耐受性、药物分子的后期多样化和放大是重要的实用特征。

  DOI：

  10.1021/acs.orglett.3c00650

文献信息

• Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124
  作者：Douglas S. Auld、Scott Lovell、Natasha Thorne、Wendy A. Lea、David J. Maloney、Min Shen、Ganesha Rai、Kevin P. Battaile、Craig J. Thomas、Anton Simeonov、Robert P. Hanzlik、James Inglese

  DOI：10.1073/pnas.0909141107

  日期：2010.3.16

  Firefly luciferase (FLuc), an ATP-dependent bioluminescent reporter enzyme, is broadly used in chemical biology and drug discovery assays. PTC124 (Ataluren; (3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid) discovered in an FLuc-based assay targeting nonsense codon suppression, is an unusually potent FLuc-inhibitor. Paradoxically, PTC124 and related analogs increase cellular FLuc activity levels by posttranslational stabilization. In this study, we show that FLuc inhibition and stabilization is the result of an inhibitory product formed during the FLuc-catalyzed reaction between its natural substrate, ATP, and PTC124. A 2.0 Å cocrystal structure revealed the inhibitor to be the acyl-AMP mixed-anhydride adduct PTC124-AMP, which was subsequently synthesized and shown to be a high-affinity multisubstrate adduct inhibitor (MAI; K _D  = 120 pM) of FLuc. Biochemical assays, liquid chromatography/mass spectrometry, and near-attack conformer modeling demonstrate that formation of this novel MAI is absolutely dependent upon the precise positioning and reactivity of a key meta -carboxylate of PTC124 within the FLuc active site. We also demonstrate that the inhibitory activity of PTC124-AMP is relieved by free coenzyme A, a component present at high concentrations in luciferase detection reagents used for cell-based assays. This explains why PTC124 can appear to increase, instead of inhibit, FLuc activity in cell-based reporter gene assays. To our knowledge, this is an unusual example in which the “off-target” effect of a small molecule is mediated by an MAI mechanism.

  萤火虫荧光酶（FLuc）是一种依赖ATP的生物发光报告酶，在化学生物学和药物发现实验中被广泛使用。PTC124（Ataluren；（3-[5-(2-氟苯基)-1,2,4-噁二唑-3-基]苯甲酸）是在基于FLuc的抑制无义密码子的荧光酶实验中发现的一种异常强效的FLuc抑制剂。矛盾的是，PTC124和相关类似物通过后转录稳定化增加了细胞内FLuc活性水平。在这项研究中，我们展示了FLuc的抑制和稳定是由FLuc催化的反应产生的一种抑制性产物，该反应发生在其天然底物ATP和PTC124之间。2.0 Å的共晶结构显示抑制剂是酰-AMP混合酸酐加合物PTC124-AMP，随后合成并表明它是FLuc的高亲和力多底物加合物抑制剂（MAI；KD = 120 pM）。生化测定、液相色谱/质谱和近攻击构象建模表明，这种新型MAI的形成绝对依赖于PTC124的关键meta-羧酸在FLuc活性位点内的精确定位和反应性。我们还证明了PTC124-AMP的抑制活性可以通过游离辅酶A来解除，后者是细胞基础实验中用于荧光酶检测试剂的高浓度成分。这解释了为什么PTC124在细胞基础报告基因实验中似乎会增加而不是抑制FLuc活性。据我们所知，这是一个罕见的例子，其中小分子的“非靶效应”是通过MAI机制介导的。
• Compounds for Nonsense Suppression, and Methods for Their Use
  申请人：Almstead Neil G.

  公开号：US20090253699A1

  公开（公告）日：2009-10-08

  The present invention relates to methods, compounds, and compositions for treating or preventing diseases associated with nonsense mutations in an mRNA by administering the compounds or compositions of the present invention. More particularly, the present invention relates to methods, compounds, and compositions for suppressing premature translation termination associated with a nonsense mutation in an mRNA.

  本发明涉及使用本发明的化合物或组合物治疗或预防与mRNA中无意义突变相关的疾病的方法、化合物和组合物。更具体地，本发明涉及用于抑制与mRNA中无意义突变相关的早期翻译终止的方法、化合物和组合物。
• METHODS FOR THE PRODUCTION OF FUNCTIONAL PROTEIN FROM DNA HAVING A NONSENSE MUTATION AND THE TREATMENT OF DISORDERS ASSOCICATED THEREWITH
  申请人：Almstead Neil G.

  公开号：US20110046136A1

  公开（公告）日：2011-02-24

  The present invention relates to functional proteins encoded by nucleic acid sequences comprising a nonsense mutation. The present invention also relates to methods for the production of functional proteins encoded by nucleic acid sequences comprising a nonsense mutation and the use of such proteins for prevention, management and/or treatment of diseases associated with a nonsense mutation(s) in a gene.

  本发明涉及由核酸序列编码的功能性蛋白质，其中包括一个无意义突变。本发明还涉及用于生产由包含无意义突变的核酸序列编码的功能性蛋白质的方法，以及利用这些蛋白质预防、管理和/或治疗与基因中的无意义突变相关的疾病。
• METHODS FOR THE PRODUCTION OF FUNCTIONAL PROTEIN FROM DNA HAVING A NONSENSE MUTATION AND THE TREATMENT OF DISORDERS ASSOCIATED THEREWITH
  申请人：PTC THERAPEUTICS, INC

  公开号：US20160199357A1

  公开（公告）日：2016-07-14

  The present invention relates to functional proteins encoded by nucleic acid sequences comprising a nonsense mutation. The present invention also relates to methods for the production of functional proteins encoded by nucleic acid sequences comprising a nonsense mutation and the use of such proteins for prevention, management and/or treatment of diseases associated with a nonsense mutation(s) in a gene.

  本发明涉及由包含无意义突变的核酸序列编码的功能蛋白质。本发明还涉及用于生产由包含无意义突变的核酸序列编码的功能蛋白质的方法，并使用这些蛋白质预防、管理和/或治疗与基因中的无意义突变相关的疾病。
• Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases
  申请人：PTC Therapeutics, Inc.

  公开号：EP2301536A1

  公开（公告）日：2011-03-30

  The present invention relates to methods, compounds, and compositions for treating or preventing diseases associated with nonsense mutations in an mRNA by administering the compounds or compositions of the present invention. More particularly, the present invention relates to methods, compounds, and compositions for suppressing premature translation termination associated with a nonsense mutation in an mRNA.

  本发明涉及通过施用本发明的化合物或组合物治疗或预防与 mRNA 中无义突变相关的疾病的方法、化合物和组合物。更具体地说，本发明涉及抑制与 mRNA 中无义突变相关的过早翻译终止的方法、化合物和组合物。