2-[(5,6-Diphenylfuro[2,3-D]pyrimidin-4-YL)amino]ethanol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃
• 英文名称: 2-[(5,6-Diphenylfuro[2,3-D]pyrimidin-4-YL)amino]ethanol
• 化学式: C₂₀H₁₇N₃O₂
• 分子量: 331.374
• InChiKey: UQHINZSKNAAVOZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  71.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5,6-二苯基-3H-呋喃并[2,3-d]嘧啶-4-酮 在 三氯氧磷 作用下， 以 乙醇 为溶剂， 反应 10.0h， 生成 2-[(5,6-Diphenylfuro[2,3-D]pyrimidin-4-YL)amino]ethanol
  参考文献：
  名称：

  Structure-Based Design of Novel Chk1 Inhibitors:  Insights into Hydrogen Bonding and Protein−Ligand Affinity

  摘要：

  We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition.

  DOI：

  10.1021/jm049022c

文献信息

• Identification, SAR Studies, and X-ray Co-crystallographic Analysis of a Novel Furanopyrimidine Aurora Kinase A Inhibitor
  作者：Mohane Selvaraj Coumar、Ming-Tsung Tsai、Chang-Ying Chu、Biing-Jiun Uang、Wen-Hsing Lin、Chun-Yu Chang、Teng-Yuan Chang、Jiun-Shyang Leou、Chi-Huang Teng、Jian-Sung Wu、Ming-Yu Fang、Chun-Hwa Chen、John T.-A. Hsu、Su-Ying Wu、Yu-Sheng Chao、Hsing-Pang Hsieh

  DOI：10.1002/cmdc.200900339

  日期：2010.2.1

  simple method for the identification of novel Aurora kinase A inhibitors through substructure searching of an in‐house compound library to select compounds for testing. A hydrazone fragment conferring Aurora kinase activity and heterocyclic rings most frequently reported in kinase inhibitors were used as substructure queries to filter the in‐house compound library collection prior to testing. Five

  本文中，我们揭示了一种通过内部化合物库的亚结构搜索来鉴定新的Aurora激酶A抑制剂的简单方法，以选择要测试的化合物。赋予Aurora激酶活性的片段和激酶抑制剂中最常报告的杂环用作子结构查询，以在测试前过滤内部化合物库的馆藏。五个新的系列的极光激酶抑制剂是通过这种策略识别与IC 50个值范围为约300Ñ中号至〜15μ中号，通过从~125 000化合物数据库仅测试133的化合物。最有效的化合物呋喃并嘧啶衍生物与IC的结构活性关系研究和X射线共晶体分析50的309的n值中号朝向极光激酶A，进行了。通过这些研究获得的知识可能有助于将来设计有效的Aurora激酶抑制剂。
• [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。
• TARGETING AN HIV-1 NEF-HOST CELL KINASE COMPLEX
  申请人：Emert-Sedlak Lori

  公开号：US20110190241A1

  公开（公告）日：2011-08-04

  Drug candidates for inhibition of HIV-I replication can target Src family kinases (SFK), such as Hck, that interact with Nef protein of the virus. Compounds characterized by such inhibitory activity were identified via an assay for kinase activity of an SFK in a Nef:SFK complex. Illustrative of inhibitors identified using the kinase assay are various 2,3-diaminoquinaxolines and furo[2,3-d]pyrimidines. The inventive inhibitors were found to arrest HIV-I viral replication in vitro.

  用于抑制HIV-I复制的药物候选物可以针对Src家族激酶（SFK），如与病毒的Nef蛋白相互作用的Hck进行靶向。通过对Nef:SFK复合物中SFK的激酶活性进行测定，鉴定了具有这种抑制活性的化合物。使用激酶测定鉴定的抑制剂的例子包括各种2,3-二氨基喹啉和呋喃[2,3-d]嘧啶。这些创新的抑制剂被发现可以在体外阻止HIV-I病毒的复制。
• 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。
• CH-01 is a Hypoxia-Activated Prodrug That Sensitizes Cells to Hypoxia/Reoxygenation Through Inhibition of Chk1 and Aurora A
  作者：Cindy Cazares-Körner、Isabel M. Pires、I. Diane Swallow、Samuel C. Grayer、Liam J. O’Connor、Monica M. Olcina、Martin Christlieb、Stuart J. Conway、Ester M. Hammond

  DOI：10.1021/cb4001537

  日期：2013.7.19

  The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability.