3-(3,5-二甲基-4-异恶唑基)-5-羟基-α-苯基苯甲醇 | 1429129-68-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 3-(3,5-二甲基-4-异恶唑基)-5-羟基-α-苯基苯甲醇
• 英文名称: 3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[hydroxyl(phenyl)methyl]phenol
• 英文别名: 3-(3,5-dimethylisoxazol-4-yl)-5-(hydroxy(phenyl)methyl)phenol；OFXBD02；Oxfbd02；3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-[hydroxy(phenyl)methyl]phenol
• CAS: 1429129-68-9
• 化学式: C₁₈H₁₇NO₃
• 分子量: 295.338
• InChiKey: FEQUIPXIENTMJN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  66.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(3,5-二甲基-4-异恶唑基)-5-羟基-α-苯基苯甲醇 在 manganese(IV) oxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 53.0h， 以84%的产率得到(3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl)(phenyl)methanone
  参考文献：
  名称：

  Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

  摘要：

  The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

  DOI：

  10.1021/jm301588r
• 作为产物：
  描述：

  3-溴-5-羟基苯甲醛 在 sodium carbonate 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 4.0h， 生成 3-(3,5-二甲基-4-异恶唑基)-5-羟基-α-苯基苯甲醇
  参考文献：
  名称：

  BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability

  摘要：

  Ligands for the bromodomain and extra terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the ReIA subunit of NF-kappa B, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t(1/2) = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBDO4 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t(1/2) = 388 min). (C) 2018 The Authors. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2018.05.003

文献信息

• [EN] FLUOROGENIC PROTECTING GROUP<br/>[FR] GROUPE DE PROTECTION FLUOROGÈNE
  申请人：ISIS INNOVATION

  公开号：WO2015071665A1

  公开（公告）日：2015-05-21

  A fluorogenic compound comprising a biologically active component and a hypoxia- activated protecting group which is fluorogenic. The biologically active component is bound to the fluorogenic component at an active binding position such that activity of the biologically active compound is suppressed until the protecting group is released. The protecting group is cleaved under hypoxic conditions, releasing the active compound and a fluorescent compound. The compounds can therefore be used in the treatment of hypoxia- related disease and disorder, such as tumour, and enable imaging of the release of the biologically active compound.

  一种荧光化合物，包括生物活性成分和一种低氧活化保护基团，该保护基团具有荧光性。生物活性成分与荧光性成分在活性结合位点上结合，从而抑制生物活性化合物的活性，直到保护基团被释放。在缺氧条件下，保护基团被割裂，释放出活性化合物和荧光化合物。因此，这些化合物可用于治疗与缺氧相关的疾病和障碍，如肿瘤，并能够成像生物活性化合物的释放。
• [EN] CYCLIC-AMP RESPONSE ELEMENT BINDING PROTEIN (CBP) AND/OR ADENOVIRAL E1A BINDING PROTEIN OF 300 KDA (P300) DEGRADATION COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSÉS DE DÉGRADATION DE PROTÉINE DE LIAISON À L'ÉLÉMENT DE RÉPONSE D'AMP CYCLIQUE (CBP) ET/OU PROTÉINE DE LIAISON E1A ADÉNOVIRALE DE 300 KDA (P300) ET MÉTHODES D'UTILISATION
  申请人：CULLGEN SHANGHAI INC

  公开号：WO2022042707A1

  公开（公告）日：2022-03-03

  Provided are bivalent compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the bivalent compounds, and methods of use the bivalent compounds for the treatment of certain disease in a subject in need thereof, and methods for identifying such bivalent compounds.

  提供双价化合物（例如，双官能团小分子化合物），包含一种或多种双价化合物的组合物，以及使用双价化合物治疗需要的患者某些疾病的方法，以及鉴定此类双价化合物的方法。
• FLUOROGENIC PROTECTING GROUP
  申请人：ISIS INNOVATION LIMITED

  公开号：US20160264558A1

  公开（公告）日：2016-09-15

  A fluorogenic compound comprising a biologically active component and a hypoxia-activated protecting group which is fluorogenic. The biologically active component is bound to the fluorogenic component at an active binding position such that activity of the biologically active compound is suppressed until the protecting group is released. The protecting group is cleaved under hypoxic conditions, releasing the active compound and a fluorescent compound. The compounds can therefore be used in the treatment of hypoxia-related disease and disorder, such as tumour, and enable imaging of the release of the biologically active compound.

  一种荧光化合物，包括生物活性组分和一种氧化缺乏激活保护基团，该保护基团是荧光的。生物活性组分与荧光组分在活性结合位点结合，使生物活性化合物的活性被抑制，直到保护基团被释放。在缺氧条件下，保护基团被裂解，释放活性化合物和荧光化合物。因此，这些化合物可以用于治疗与缺氧相关的疾病和障碍，如肿瘤，并能够成像生物活性化合物的释放。
• BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability
  作者：Laura E. Jennings、Matthias Schiedel、David S. Hewings、Sarah Picaud、Corentine M.C. Laurin、Paul A. Bruno、Joseph P. Bluck、Amy R. Scorah、Larissa See、Jessica K. Reynolds、Mustafa Moroglu、Ishna N. Mistry、Amy Hicks、Pavel Guzanov、James Clayton、Charles N.G. Evans、Giulia Stazi、Philip C. Biggin、Anna K. Mapp、Ester M. Hammond、Philip G. Humphreys、Panagis Filippakopoulos、Stuart J. Conway

  DOI：10.1016/j.bmc.2018.05.003

  日期：2018.7

  Ligands for the bromodomain and extra terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the ReIA subunit of NF-kappa B, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t(1/2) = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBDO4 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t(1/2) = 388 min). (C) 2018 The Authors. Published by Elsevier Ltd.
• Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands
  作者：David S. Hewings、Oleg Fedorov、Panagis Filippakopoulos、Sarah Martin、Sarah Picaud、Anthony Tumber、Christopher Wells、Monica M. Olcina、Katherine Freeman、Andrew Gill、Alison J. Ritchie、David W. Sheppard、Angela J. Russell、Ester M. Hammond、Stefan Knapp、Paul E. Brennan、Stuart J. Conway

  DOI：10.1021/jm301588r

  日期：2013.4.25

  The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.