9-Pent-4-ynyl-8-[(3,4,5-trimethoxyphenyl)methyl]purine-2,6-diamine | 422508-39-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 9-Pent-4-ynyl-8-[(3,4,5-trimethoxyphenyl)methyl]purine-2,6-diamine
• 英文别名: 9-pent-4-ynyl-8-[(3,4,5-trimethoxyphenyl)methyl]purine-2,6-diamine
• CAS: 422508-39-2
• 化学式: C₂₀H₂₄N₆O₃
• 分子量: 396.449
• InChiKey: SIJVESRYDUWDHT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  9-Pent-4-ynyl-8-[(3,4,5-trimethoxyphenyl)methyl]purine-2,6-diamine 在 四(三苯基膦)钯 、 二碘甲烷 、 亚硝酸异戊酯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 2-cyano-9-pent-4-ynyl-8-(3,4,5-trimethoxy-benzyl)-9H-purin-6-ylamine
  参考文献：
  名称：

  Development of a Purine-Scaffold Novel Class of Hsp90 Binders that Inhibit the Proliferation of Cancer Cells and Induce the Degradation of Her2 Tyrosine Kinase

  摘要：

  The first published synthesis and characterization of a purine-scaffold library of hsp90 inhibitors is presented. The purine-scaffold represents a platform for the creation of easily synthesizable and derivatizable soluble molecules that are amenable for oral administration. The most active compound of the series (71) exhibits binding to hsp90 comparable to the natural product derivative 17AAG that is now in Phase I clinical trial as a cancer therapeutic. 71 Induces the degradation of Her2 tyrosine kinase and arrests the MCF-7 breast cancer cell line at low micromolar concentrations (IC50 = 2 muM). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00253-5
• 作为产物：
  描述：

  3,4,5-三甲氧基苯乙酸 在 吡啶 、 sodium hydroxide 、 三聚氟氰 、 偶氮二甲酸二叔丁酯 、 三苯基膦 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 22.5h， 生成 9-Pent-4-ynyl-8-[(3,4,5-trimethoxyphenyl)methyl]purine-2,6-diamine
  参考文献：
  名称：

  Development of a Purine-Scaffold Novel Class of Hsp90 Binders that Inhibit the Proliferation of Cancer Cells and Induce the Degradation of Her2 Tyrosine Kinase

  摘要：

  The first published synthesis and characterization of a purine-scaffold library of hsp90 inhibitors is presented. The purine-scaffold represents a platform for the creation of easily synthesizable and derivatizable soluble molecules that are amenable for oral administration. The most active compound of the series (71) exhibits binding to hsp90 comparable to the natural product derivative 17AAG that is now in Phase I clinical trial as a cancer therapeutic. 71 Induces the degradation of Her2 tyrosine kinase and arrests the MCF-7 breast cancer cell line at low micromolar concentrations (IC50 = 2 muM). (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00253-5

文献信息

• Small molecule compositions for binding to hsp90
  申请人：——

  公开号：US20040102458A1

  公开（公告）日：2004-05-27

  Structural differences in binding pockets of members of the HSP90 family can be exploited to achieve differential degradation of kinases and other signaling proteins through the use of designed small molecules which interact with the N-terminal binding pocket with an affinity which is greater than ADP and different from the ansamycin antibiotics for at least one species of the HSP90 family. Moreover, these small molecules can be designed to be soluble in aqueous media, thus providing a further advantage over the use of ansamycin antibiotics. Pharmaceutical compositions can be formulated containing a pharmaceutically acceptable carrier and a molecule that includes a binding moiety which binds to the N-terminal pocket of at least one member of the HSP90 family of proteins. Such binding moieties were found to have antiproliferative activity against tumor cells which are dependent on proteins requiring chaperones of the HSP90 family for their function. Different chemical species have different activity, however, allowing the selection of, for example Her2 degradation without degradation of Raf kinase. Thus, the binding moieties possess an inherent targeting capacity. In addition, the small molecules can be linked to targeting moieties to provide targeting of the activity to specific classes of cells. Thus, the invention further provides a method for treatment of diseases, including cancers, by administration of these compositions. Dimeric forms of the binding moieties may also be employed.

  HSP90家族成员的结构差异可以被利用来通过设计的小分子与N端结合口袋相互作用，以比ADP更高的亲和力和与ansamycin抗生素至少一种HSP90家族成员不同的亲和力，从而实现激酶和其他信号蛋白的差异降解。此外，这些小分子可以被设计成在水性介质中溶解，因此比使用ansamycin抗生素具有进一步的优势。可以制定含有药学上可接受的载体和包含结合基团的分子的制剂，该结合基团结合至少一种HSP90家族蛋白的N端口袋。发现这种结合基团对于依赖于HSP90家族分子伴侣蛋白的功能的肿瘤细胞具有抗增殖活性。不同的化学物种具有不同的活性，因此可以选择降解Her2而不降解Raf激酶。因此，这些结合基团具有固有的靶向能力。此外，小分子可以连接到靶向基团上，以提供对特定类别的细胞的靶向活性。因此，该发明还提供了一种通过给予这些组合物治疗疾病，包括癌症的方法。结合基团的二聚体形式也可以被使用。
• COMPOSITIONS CONTAINING PURINE DERIVATIVES FOR BINDING TO HSP90
  申请人：Sloan-Kettering Institute For Cancer Research

  公开号：EP1335920B1

  公开（公告）日：2013-04-03
• SMALL MOLECULE COMPOSITIONS FOR BINDING TO HSP90
  申请人：Sloan-Kettering InstituteFor Cancer Research

  公开号：EP1335920A2

  公开（公告）日：2003-08-20
• EP1335920A4
  申请人：——

  公开号：EP1335920A4

  公开（公告）日：2005-08-17
• US7439359B2
  申请人：——

  公开号：US7439359B2

  公开（公告）日：2008-10-21