8-((2,4-dimethylphenyl)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-((2,4-dimethylphenyl)thio)-9-(pent-4-yn-1-yl)-9H-purin-6-amine
• 英文别名: 8-(2,4-Dimethyl-phenylsulfanyl)-9-pent-4-ynyl-9H-purin-6-ylamine；8-(2,4-dimethylphenyl)sulfanyl-9-pent-4-ynylpurin-6-amine
• 化学式: C₁₈H₁₉N₅S
• 分子量: 337.448
• InChiKey: WLYXAWLTUOYKMO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 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：

  2,4-二甲基-1-碘苯 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-((2,4-dimethylphenyl)thio)-9-(pent-4-yn-1-yl)-9H-purin-6-amine 、 8-((2,4-dimethylphenyl)thio)-3-(pent-4-yn-1-yl)-3H-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

• 一组具有结合gp96蛋白的能力的化合物及其在 抗乳腺癌中的应用
  申请人：北京中科永邦生物科技有限公司

  公开号：CN103570717B

  公开（公告）日：2016-05-11

  本发明公开了一组具有结合gp96蛋白的能力的化合物及其在抗乳腺癌中的应用。本发明提供了一组化合物，为如下（a）或（b）：（a）式（Ⅲ）所示的化合物A3、式（Ⅱ）所示的化合物A2、式（Ⅳ）所示的化合物A4、式（Ⅵ）所示的化合物A6、式（Ⅴ）所示的化合物A5或式（Ⅰ）所示的化合物A1；（b）将（a）所述的化合物进行官能团替换且具有相同功能的腺嘌呤类衍生物。本发明提供的腺嘌呤衍生物抑制gp96后能明显下调HER2，抑制乳腺癌细胞增殖、促进乳腺癌细胞凋亡，降低乳腺癌细胞的侵袭性，对体内乳腺癌肿瘤具有明显的抑制作用。本发明对于癌症的治疗，特别是乳腺癌的治疗具有重大价值。
• 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。
• Evaluation of 8-Arylsulfanyl, 8-Arylsulfoxyl, and 8-Arylsulfonyl Adenine Derivatives as Inhibitors of the Heat Shock Protein 90
  作者：Laura Llauger、Huazhong He、Joungnam Kim、Julia Aguirre、Neal Rosen、Ulf Peters、Peter Davies、Gabriela Chiosis

  DOI：10.1021/jm049012b

  日期：2005.4.1

  Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC50 = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.
• 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.