3-((4,6-dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-thio)aniline | 1268273-75-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 3-((4,6-dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-thio)aniline
• 英文别名: 3-[4,6-Dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]sulfanylaniline
• CAS: 1268273-75-1
• 化学式: C₁₇H₂₃N₅O₂S
• 分子量: 361.468
• InChiKey: CKXCJTBDPUVSDR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-((4,6-dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-thio)aniline 在 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 生成 2-amino-N-(3-((4,6-dimethoxy-2-(4-methylpiperazin-1-yl)-pyrimidin-5-yl)thio)phenyl)acetamide
  参考文献：
  名称：

  热休克蛋白 70 抑制剂。2. 2,5'-硫代二嘧啶、5-（苯硫基）嘧啶、2-（吡啶-3-基硫基）嘧啶和 3-（苯硫基）吡啶作为热激蛋白 70 变构位点的可逆结合剂

  摘要：

  热休克蛋白70（Hsp70）抑制剂的发现和开发是目前癌症领域的热门话题。在本期的前一篇论文 (10.1021/jm401551n) 中，我们描述了第一个 Hsp70 抑制剂类的结构-活性关系研究，这些抑制剂经过合理设计以结合位于蛋白质 N 端结构域的新型变构口袋。这些配体含有丙烯酰胺，以利用嵌入变构口袋中的活性半胱氨酸，并在结合时充当共价蛋白质修饰剂。在这里，我们围绕不可逆抑制剂支架进行化学修饰，以证明共价修饰不是此类化合物活性的必要条件。该研究确定了衍生物27c，它模拟了不可逆抑制剂在可比浓度下的生物效应。总的来说，背靠背手稿描述了第一个药效团，这些药效团与 Hsp70 中从未探索过的口袋有利地和选择性地相互作用，并为 Hsp70 定向配体的癌症导向开发提供了新的蓝图。

  DOI：

  10.1021/jm401552y
• 作为产物：
  描述：

  2-氯-4,6-二甲氧基嘧啶 在 copper(l) iodide 、 新铜试剂 potassium phosphate 、 N-碘代丁二酰亚胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 21.0h， 生成 3-((4,6-dimethoxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-thio)aniline
  参考文献：
  名称：

  [EN] HEAT SHOCK PROTEIN BINDING COMPOUNDS, COMPOSITIONS, AND METHODS FOR MAKING AND USING SAME
  [FR] COMPOSÉS DE LIAISON À UNE PROTÉINE DE CHOC THERMIQUE, COMPOSITIONS ET PROCÉDÉS POUR LES FABRIQUER ET LES UTILISER

  摘要：

  公开号：

  WO2011022440A9

文献信息

• Copper mediated coupling of 2-(piperazine)-pyrimidine iodides with aryl thiols using Cu(I)thiophene-2-carboxylate
  作者：Liza Shrestha、Hardik J. Patel、Yanlong Kang、Sahil Sharma、Gabriela Chiosis、Tony Taldone

  DOI：10.1016/j.tetlet.2017.10.041

  日期：2017.11

  copper-mediated synthesis of diaryl sulfides utilizing Cu(I)-thiophene-2-carboxylate (CuTC) is described. We demonstrate the use of CuTC as a soluble, non-basic catalyst in the coupling of aryl iodides and aryl thiols in the synthesis of synthetically advanced diaryl sulfides. This method allows for the successful coupling of challenging substrates including ortho-substituted and heteroaryl iodides and thiols

  描述了利用Cu（I）-噻吩-2-羧酸盐（CuTC）的铜介导的二芳基硫醚的合成。我们证明了在合成高级二芳基硫醚的合成中，CuTC作为可溶性，非碱性催化剂在芳基碘化物和芳基硫醇的偶联中的应用。这种方法可以成功地耦合包括邻位在内的具有挑战性的基材-取代的和杂芳基碘化物和硫醇。另外，这里使用的大多数芳基碘化物底物包含与嘧啶，吡啶或苯环键合的特权哌嗪支架，因此该方法允许将复杂的哌嗪支架加工成具有生物学意义的分子。此处描述的方法可以将后期结构的多样性纳入到含有哌嗪环的二芳基硫醚中，从而提高了可用于SAR研究的衍生物的数量和性质。
• HEAT SHOCK PROTEIN BINDING COMPOUNDS, COMPOSITIONS, AND METHODS FOR MAKING AND USING SAME
  申请人：Chiosis Gabriela

  公开号：US20120252818A1

  公开（公告）日：2012-10-04

  The present subject matter relates to a compound represented by the general formula (I) or (I′) or a pharmacologically acceptable salt thereof; pharmaceutical compositions containing at least one of these compounds; methods of making at least one of these compounds; methods of using at least one of these compounds for treating and/or preventing various cancers and/or proliferation disorders; methods of using at least one of these compounds for monitoring the effectiveness of an anticancer therapy against various cancers. In one embodiment, the subject matter relates to compounds that bind with a level of specificity to heat shock protein 70 (Hsp70). In another embodiment, the subject matter relates to compounds that bind with a level of specificity to inhibit both heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70).

  本主题涉及一种由通式(I)或(I′)表示的化合物或其药学上可接受的盐；包含至少一种这些化合物的制药组合物；制备至少一种这些化合物的方法；使用至少一种这些化合物治疗和/或预防各种癌症和/或增殖障碍的方法；使用至少一种这些化合物监测抗癌治疗对各种癌症的有效性的方法。在一种实施方式中，本主题涉及与热休克蛋白70（Hsp70）具有特异性结合的化合物。在另一种实施方式中，本主题涉及与具有特异性抑制热休克蛋白70（Hsp70）和热休克同源蛋白70（Hsc70）的化合物的结合。
• Heat shock protein binding compounds, compositions, and methods for making and using same
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：US10052325B2

  公开（公告）日：2018-08-21

  The present subject matter relates to a compound represented by the general formula (I) or (I′) or a pharmacologically acceptable salt thereof; pharmaceutical compositions containing at least one of these compounds; methods of making at least one of these compounds; methods of using at least one of these compounds for treating and/or preventing various cancers and/or proliferation disorders; methods of using at least one of these compounds for monitoring the effectiveness of an anticancer therapy against various cancers. In one embodiment, the subject matter relates to compounds that bind with a level of specificity to heat shock protein 70 (Hsp70). In another embodiment, the subject matter relates to compounds that bind with a level of specificity to inhibit both heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70).

  本主题涉及通式(I)或(I′)代表的化合物或其药理学上可接受的盐；含有至少一种这些化合物的药物组合物；制造至少一种这些化合物的方法；使用至少一种这些化合物治疗和/或预防各种癌症和/或增殖障碍的方法；使用至少一种这些化合物监测抗癌疗法对各种癌症的疗效的方法。在一个实施方案中，该主题涉及与热休克蛋白 70（Hsp70）具有一定特异性结合的化合物。在另一个实施方案中，本发明涉及的化合物具有一定程度的特异性，可同时抑制热休克蛋白70（Hsp70）和热休克同源蛋白70（Hsc70）。
• Heat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5-(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70
  作者：Yanlong Kang、Tony Taldone、Hardik J. Patel、Pallav D. Patel、Anna Rodina、Alexander Gozman、Ronnie Maharaj、Cristina C. Clement、Maulik R. Patel、Jeffrey L. Brodsky、Jason C. Young、Gabriela Chiosis

  DOI：10.1021/jm401551n

  日期：2014.2.27

  Heat shock protein 70 (Hsp70) is an important emerging. cancer. target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5'-thiodipyrimidine and 5-(phenylthio)-pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives 17a and 20a, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics.
• 2-(Pyrimidin-5-yl)-thiopyrimidine derivatives as Hsp70 and Hsc70 modulators for the treatment of proliferative disorders
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：EP2467142B1

  公开（公告）日：2016-09-21