N-(tert-butyl)-2-chloro-9H-purin-6-amine | 1184303-77-2

• 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: N-(tert-butyl)-2-chloro-9H-purin-6-amine
• 英文别名: N-tert-butyl-2-chloro-7H-purin-6-amine
• CAS: 1184303-77-2
• 化学式: C₉H₁₂ClN₅
• 分子量: 225.681
• InChiKey: XYCSYAIZCNEYRE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 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-氨基噻吩 、 N-(tert-butyl)-2-chloro-9H-purin-6-amine 在 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium tert-butylate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 叔丁醇 为溶剂， 反应 16.0h， 生成 N⁶-(tert-butyl)-N²-(thiophen-3-yl)-9H-purine-2,6-diamine
  参考文献：
  名称：

  二氨基嘌呤化学型的药物化学优化：寻找布氏锥虫抑制剂的先导物。

  摘要：

  非洲人类锥虫病 (HAT) 或昏睡病是由原生动物寄生虫布氏锥虫引起的，并通过受感染的采采蝇叮咬传播。如果不治疗，这种疾病被认为是致命的。为了鉴定针对布氏锥虫的新化学型，之前我们鉴定了 797 种有效的激酶靶向抑制剂，这些抑制剂分为 59 个簇和 53 种单一化合物，其选择性至少是 HepG2 细胞的 100 倍。从这组命中中，鉴定了一组二氨基嘌呤衍生的化合物。在此，我们报告了我们的药物化学研究，涉及探索围绕高通量筛选 (HTS) 命中之一N 2 -(噻吩-3-基)-的结构-活性和结构-性质关系N 6 -(2,2,2-三氟乙基)-9 H-嘌呤-2,6-二胺( 1，NEU-1106)。这项工作导致鉴定出一种有效的先导化合物（4aa，NEU-4854），其具有改善的体外吸收、分布、代谢和排泄 (ADME) 特性，并已进展为体外抗寄生虫活性的概念验证翻译到体内功效。

  DOI：

  10.1021/acs.jmedchem.0c01017
• 作为产物：
  描述：

  2,6-二氯-9-(四氢-2H-吡喃-2-基)-9h-嘌呤 在 三氟乙酸 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 16.0h， 生成 N-(tert-butyl)-2-chloro-9H-purin-6-amine
  参考文献：
  名称：

  Synthesis and evaluation of 18F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression

  摘要：

  Type II topoisomerase (Topo-II) is an ATP-dependent enzyme that is essential in the transcription, replication, and chromosome segregation processes and, as such, represents an attractive target for cancer therapy. Numerous studies indicate that the response to treatment with Topo-II inhibitors is highly dependent on both the levels and the activity of the enzyme. Consequently, a non-invasive assay to measure tumoral Topo-II levels has the potential to differentiate responders from non-responders. With the ultimate goal of developing a radiofluorinated tracer for positron emission tomography (PET) imaging, we have designed, synthesized, and evaluated a set of fluorinated compounds based on the structure of the ATP-competitive Topo-II inhibitor QAP1. Compounds 18 and 19b showed inhibition of Topo-II in in vitro assays and exhibited moderate, Topo-II level dependent cytotoxicity in SK-BR-3 and MCF-7 cell lines. Based on these results, F-18-labeled analogs of these two compounds were synthesized and evaluated as PET probes for imaging Topo-II overexpression in mice bearing SK-BR-3 xenografts. [F-18]-18 and [F-18]-19b were synthesized from their corresponding protected tosylated derivatives by fluorination and subsequent deprotection. Small animal PET imaging studies indicated that both compounds do not accumulate in tumors and exhibit poor pharmacokinetics, clearing from the blood pool very rapidly and getting metabolized over. The insights gained from the current study will surely aid in the design and construction of future generations of PET agents for the non-invasive delineation of Topo-II expression. (c) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.09.019

文献信息

• Discovery of a new class of catalytic topoisomerase II inhibitors targeting the ATP-binding site by structure based design. Part I
  作者：Pascal Furet、Joseph Schoepfer、Thomas Radimerski、Patrick Chène

  DOI：10.1016/j.bmcl.2009.06.034

  日期：2009.8

  the ATP-binding site of the enzyme. Searching the Novartis compound collection for molecules containing this purine motif has allowed the identification of two micromolar hits providing access to a new class of catalytic topoisomerase II inhibitors.

  拓扑异构酶II是肿瘤学中经过验证的靶标。在阻断该酶功能的不同方式中，抑制其ATPase活性的研究相对较少。为了鉴定一种新型的拓扑异构酶II抑制剂，并通过这种机制发挥作用，我们设计了一种针对该酶ATP结合位点的嘌呤抑制剂支架。在诺华公司的化合物集合中搜索包含该嘌呤基序的分子，可以鉴定出两个微摩尔分子，可提供一种新型的催化拓扑异构酶II抑制剂。
• Synthesis and evaluation of 18F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression
  作者：Pierre Daumar、Brian M. Zeglis、Nicholas Ramos、Vadim Divilov、Kuntal Kumar Sevak、NagaVaraKishore Pillarsetty、Jason S. Lewis

  DOI：10.1016/j.ejmech.2014.09.019

  日期：2014.10

  Type II topoisomerase (Topo-II) is an ATP-dependent enzyme that is essential in the transcription, replication, and chromosome segregation processes and, as such, represents an attractive target for cancer therapy. Numerous studies indicate that the response to treatment with Topo-II inhibitors is highly dependent on both the levels and the activity of the enzyme. Consequently, a non-invasive assay to measure tumoral Topo-II levels has the potential to differentiate responders from non-responders. With the ultimate goal of developing a radiofluorinated tracer for positron emission tomography (PET) imaging, we have designed, synthesized, and evaluated a set of fluorinated compounds based on the structure of the ATP-competitive Topo-II inhibitor QAP1. Compounds 18 and 19b showed inhibition of Topo-II in in vitro assays and exhibited moderate, Topo-II level dependent cytotoxicity in SK-BR-3 and MCF-7 cell lines. Based on these results, F-18-labeled analogs of these two compounds were synthesized and evaluated as PET probes for imaging Topo-II overexpression in mice bearing SK-BR-3 xenografts. [F-18]-18 and [F-18]-19b were synthesized from their corresponding protected tosylated derivatives by fluorination and subsequent deprotection. Small animal PET imaging studies indicated that both compounds do not accumulate in tumors and exhibit poor pharmacokinetics, clearing from the blood pool very rapidly and getting metabolized over. The insights gained from the current study will surely aid in the design and construction of future generations of PET agents for the non-invasive delineation of Topo-II expression. (c) 2014 Elsevier Masson SAS. All rights reserved.
• Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for <i>Trypanosoma brucei</i> Inhibitors
  作者：Baljinder Singh、Rosario Diaz-Gonzalez、Gloria Ceballos-Perez、Domingo I. Rojas-Barros、Naresh Gunaganti、Kirsten Gillingwater、Maria Santos Martinez-Martinez、Pilar Manzano、Miguel Navarro、Michael P. Pollastri

  DOI：10.1021/acs.jmedchem.0c01017

  日期：2020.9.10

  Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against Trypanosoma brucei, previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with

  非洲人类锥虫病 (HAT) 或昏睡病是由原生动物寄生虫布氏锥虫引起的，并通过受感染的采采蝇叮咬传播。如果不治疗，这种疾病被认为是致命的。为了鉴定针对布氏锥虫的新化学型，之前我们鉴定了 797 种有效的激酶靶向抑制剂，这些抑制剂分为 59 个簇和 53 种单一化合物，其选择性至少是 HepG2 细胞的 100 倍。从这组命中中，鉴定了一组二氨基嘌呤衍生的化合物。在此，我们报告了我们的药物化学研究，涉及探索围绕高通量筛选 (HTS) 命中之一N 2 -(噻吩-3-基)-的结构-活性和结构-性质关系N 6 -(2,2,2-三氟乙基)-9 H-嘌呤-2,6-二胺( 1，NEU-1106)。这项工作导致鉴定出一种有效的先导化合物（4aa，NEU-4854），其具有改善的体外吸收、分布、代谢和排泄 (ADME) 特性，并已进展为体外抗寄生虫活性的概念验证翻译到体内功效。