8-((3,4-dichlorophenyl)thio)-9-(pent-4-yn-1-yl)-9H-purin-6-amine

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 8-((3,4-dichlorophenyl)thio)-9-(pent-4-yn-1-yl)-9H-purin-6-amine
• 英文别名: 8-(3,4-Dichlorophenyl)sulfanyl-9-pent-4-ynylpurin-6-amine；8-(3,4-dichlorophenyl)sulfanyl-9-pent-4-ynylpurin-6-amine
• 化学式: C₁₆H₁₃Cl₂N₅S
• 分子量: 378.285
• InChiKey: JYNZAIBVDQDZLY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  94.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3,4-二氯碘苯 、 8-巯基腺嘌呤 在 copper(l) iodide 、 2,9-dimethyl-1,10-phenanthroline hydrate 、 caesium carbonate 、 sodium t-butanolate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.5h， 生成 8-((3,4-dichlorophenyl)thio)-9-(pent-4-yn-1-yl)-9H-purin-6-amine
  参考文献：
  名称：

  Structure–Activity Relationship in a Purine-Scaffold Compound Series with Selectivity for the Endoplasmic Reticulum Hsp90 Paralog Grp94

  摘要：

  Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC50 = 0.22 mu M) and selectivity over other paralogs (>100- and 33-fold for Hsp90 alpha/beta and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor.

  DOI：

  10.1021/acs.jmedchem.5b00197

文献信息

• SELECTIVE GRP94 INHIBITORS AND USES THEREOF
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：US20160194328A1

  公开（公告）日：2016-07-07

  The disclosure relates to novel selective Grp94 inhibitors, compositions comprising an effective amount of such compounds, and methods to treat or prevent a condition, such as cancer, comprising administering to an animal in need thereof an effective amount of such compounds.

  本公开涉及新型选择性Grp94抑制剂，包括含有有效量此类化合物的组合物，以及治疗或预防疾病的方法，例如癌症，包括向需要此类化合物的动物施用有效量此类化合物。
• Selective Grp94 inhibitors and uses thereof
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：US10421758B2

  公开（公告）日：2019-09-24

  The disclosure relates to novel selective Grp94 inhibitors, compositions comprising an effective amount of such compounds, and methods to treat or prevent a condition, such as cancer, comprising administering to an animal in need thereof an effective amount of such compounds.

  本公开涉及新型选择性 Grp94 抑制剂、包含有效量此类化合物的组合物，以及治疗或预防癌症等疾病的方法，包括向有需要的动物施用有效量的此类化合物。
• [EN] SELECTIVE GRP94 INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS SÉLECTIFS DE LA GRP94 ET LEURS UTILISATIONS
  申请人：SLOAN KETTERING INST CANCER

  公开号：WO2015023976A2

  公开（公告）日：2015-02-19

  The disclosure relates to novel selective Grp94 inhibitors, compositions comprising an effective amount of such compounds, and methods to treat or prevent a condition, such as cancer, comprising administering to an animal in need thereof an effective amount of such compounds.
• Structure–Activity Relationship in a Purine-Scaffold Compound Series with Selectivity for the Endoplasmic Reticulum Hsp90 Paralog Grp94
  作者：Hardik J. Patel、Pallav D. Patel、Stefan O. Ochiana、Pengrong Yan、Weilin Sun、Maulik R. Patel、Smit K. Shah、Elisa Tramentozzi、James Brooks、Alexander Bolaender、Liza Shrestha、Ralph Stephani、Paola Finotti、Cynthia Leifer、Zihai Li、Daniel T. Gewirth、Tony Taldone、Gabriela Chiosis

  DOI：10.1021/acs.jmedchem.5b00197

  日期：2015.5.14

  Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC50 = 0.22 mu M) and selectivity over other paralogs (>100- and 33-fold for Hsp90 alpha/beta and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor.