N¹-(6-chloropyrazin-2-yl)-N²,N²-dimethylethane-1,2-diamine | 1219957-55-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N¹-(6-chloropyrazin-2-yl)-N²,N²-dimethylethane-1,2-diamine
• 英文别名: N-(6-chloropyrazin-2-yl)-N',N'-dimethylethane-1,2-diamine；N-(6-chloropyrazin-2-yl)-N’,N’-dimethylethane-1,2-diamine；N1-(6-Chloropyrazin-2-yl)-N2,N2-dimethylethane-1,2-diamine
• CAS: 1219957-55-7
• 化学式: C₈H₁₃ClN₄
• 分子量: 200.671
• InChiKey: KXDMEFAOEAHGGY-UHFFFAOYSA-N

物化性质

• 沸点：
  317.9±42.0 °C(Predicted)
• 密度：
  1.223±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  13
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  41
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT

反应信息

• 作为反应物：
  描述：

  N¹-(6-chloropyrazin-2-yl)-N²,N²-dimethylethane-1,2-diamine 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 乙醇 、 乙二醇甲醚 为溶剂， 反应 0.34h， 生成 N¹-(6-(3-(2-aminopyrimidin-4-yl)-1H-indol-5-yl)pyrazin-2-yl)-N²,N²-dimethylethane-1,2-diamine
  参考文献：
  名称：

  Pim激酶抑制和抗增殖活性的一系列新的子午线C衍生物

  摘要：

  制备了一系列新的在C-5位置取代的子午线C衍生物。测试了这些衍生物对pim激酶的所有三个家族成员（Pim-1，Pim-2和Pim-3）的激酶抑制能力。另外，已经评估了它们对三种人白血病细胞系MV4-11，Jurkat克隆E6-1和K562的抗增殖活性。进行了吲哚的C-3和C-5位置的结构活性关系以更好地了解增强效力背后的机制。该系列中活性最高的化合物7f显示出对Pim-1激酶具有选择性的一位数纳摩尔IC 50。

  DOI：

  10.1016/j.bmcl.2014.04.035
• 作为产物：
  描述：

  2,6-二氯吡嗪 、 N,N-二甲基乙二胺 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以84%的产率得到N¹-(6-chloropyrazin-2-yl)-N²,N²-dimethylethane-1,2-diamine
  参考文献：
  名称：

  Pim激酶抑制和抗增殖活性的一系列新的子午线C衍生物

  摘要：

  制备了一系列新的在C-5位置取代的子午线C衍生物。测试了这些衍生物对pim激酶的所有三个家族成员（Pim-1，Pim-2和Pim-3）的激酶抑制能力。另外，已经评估了它们对三种人白血病细胞系MV4-11，Jurkat克隆E6-1和K562的抗增殖活性。进行了吲哚的C-3和C-5位置的结构活性关系以更好地了解增强效力背后的机制。该系列中活性最高的化合物7f显示出对Pim-1激酶具有选择性的一位数纳摩尔IC 50。

  DOI：

  10.1016/j.bmcl.2014.04.035

文献信息

• 2-Thioxothiazolidin-4-one Analogs as Pan-PIM Kinase Inhibitors
  作者：Yanghwan Yun、Victor Sukbong Hong、Seungik Jeong、Hyeonseong Choo、Shin Kim、Jinho Lee

  DOI：10.1248/cpb.c21-00264

  日期：2021.9.1

  derivatives were synthesized and evaluated as potent pan-PIM kinase inhibitors. Optimized compounds showed single-digit nanomolar IC50 values against all three PIM kinases with high selectivity over 14 other kinases. Compound 17 inhibited the growth of Molm-16 cell lines (EC50 = 14 nM) and modulated the expression of pBAD and p4EBP1 in a dose-dependent manner. Fullsize Image

  莫洛尼鼠白血病病毒 (PIM) 激酶的原病毒整合位点是参与调节多种细胞过程的原癌激酶。PIM 激酶是新药开发的有希望的靶点，因为它们在许多癌症特异性途径中发挥重要作用，例如存活、细胞凋亡、增殖、细胞周期调节和迁移。在这里，2-thioxothiazolidin-4-one 衍生物被合成并评估为有效的泛 PIM 激酶抑制剂。优化的化合物对所有三种 PIM 激酶均显示出个位数纳摩尔 IC 50值，并且选择性高于其他 14 种激酶。化合物17抑制 Molm-16 细胞系 (EC 50  = 14 nM) 的生长并以剂量依赖性方式调节 pBAD 和 p4EBP1 的表达。 全尺寸图像
• Synthesis and Evaluation of 5-(3-(Pyrazin-2-yl)benzylidene)thiazolidine-2,4-dione Derivatives as Pan–Pim Kinases Inhibitors
  作者：Jinho Lee、Jongseong Park、Victor Sukbong Hong

  DOI：10.1248/cpb.c14-00325

  日期：——

  Pim kinases play a key role in the regulation of signaling pathways including proliferation, migration, and metabolism and are a potential target for cancer therapy. A series of 5-benzylidenethiazolidine-2,4-diones were synthesized as pim kinase inhibitors. The structure–activity relationships (SAR) of the analogues in inhibiting in vitro pim kinase activity as well as the proliferation of leukemia cell lines were examined. SAR studies indicated that a hydroxyl group at the 2-position of the benzene ring of 5-benzylidenethiazolidine-2,4-dione plays an important role in the inhibitory activity against all three pim kinases and replacement with a pyrazinyl group at the 5-position of the benzene ring of 5-benzylidenethiazolidine-2,4-dione improved activity significantly. The compounds exerted anti-proliferative activity against the three leukemia cell lines we tested. The most potent compound, 5i, had an EC50 value of 0.8 µM in the MV4-11 cell line. The result of kinase profiling indicated that compound 5i was highly selective for pim-kinases.

  Pim激酶在调控包括增殖、迁移和代谢等信号通路中发挥关键作用，并且是癌症治疗的潜在靶点。一系列5-苄叉噻唑烷-2,4-二酮被合成作为pim激酶抑制剂。研究了这些类似物在体外抑制pim激酶活性和白血病细胞系增殖的结构-活性关系（SAR）。SAR研究表明，5-苄叉噻唑烷-2,4-二酮的苯环2位上的羟基在抑制所有三种pim激酶的活性中起重要作用，而将5-苄叉噻唑烷-2,4-二酮的苯环5位上的取代基替换为吡嗪基团可显著提高活性。这些化合物对我们在测试的三种白血病细胞系展现出抗增殖活性。最强的化合物5i在MV4-11细胞系中的EC50值为0.8µM。激酶谱分析结果表明，化合物5i对pim激酶具有高度选择性。
• 1,3, <scp>4‐Oxadiazole</scp> ‐2( <scp> 3 <i>H</i> </scp> )‐thione Analogs as <scp>PIM</scp> Kinase Inhibitors
  作者：Victor Sukbong Hong、Seungik Jeong、Yanghwan Yun、Hyeonseong Choo、Jongin Won、Jinho Lee

  DOI：10.1002/bkcs.12101

  日期：2020.10

  contribute to tumor growth and survival. Therefore, a potent inhibitor of PIM kinases is expected to be effective at treating hematological cancers. In the present study, several indole derivatives of 1,3,4‐oxadiazole‐2(3H)‐thione were synthesized and evaluated as PIM kinase inhibitors. Structure–activity relationship studies yielded potent inhibitors of all three PIM kinases in the single‐digit to low double‐digit

  莫洛尼鼠白血病病毒（PIM）激酶的前病毒整合位点在血液系统癌症中高度表达。它们磷酸化有助于肿瘤生长和存活的下游底物。因此，预期PIM激酶的有效抑制剂可有效治疗血液学癌症。在本研究中，合成了1,3,4-恶二唑-2（3 H）-硫酮的几种吲哚衍生物，并将其评估为PIM激酶抑制剂。结构-活性关系研究得出了所有三种PIM激酶的有效抑制剂，其单位数至低两位数纳摩尔级IC 50范围内。代表性化合物的激酶图谱显示了在其他15种激酶中的高选择性。
• 신규한 Pim 키나아제 억제제 및 이의 용도
  申请人：INDUSTRY ACADEMIC COOPERATION FOUNDATION KEIMYUNG UNIVERSITY 계명대학교 산학협력단(220040180743) BRN ▼503-82-09622

  公开号：KR20210108684A

  公开（公告）日：2021-09-03

  본 발명은 신규한 Pim 키나아제 억제제 및 이의 용도에 관한 것으로, 보다 상세하게는 Pim 키나아제 억제 활성을 가지는 신규한 1,3,4-옥시다졸-2(3H)-티온(1,3,4-Oxadiazole-2(3H)-thione) 기반 화합물 및 이를 포함하는 Pim 키나아제 억제용 조성물 또는 암 예방 또는 치료용 조성물에 관한 것이다. 본 발명의 1,3,4-옥시다졸-2(3H)-티온(1,3,4-Oxadiazole-2(3H)-thione) 기반 화합물은 낮은 농도에서도 매우 효과적으로 Pim 키나아제 억제 활성을 가지는 것을 확인하였으므로, 본 발명의 화합물은 Pim 키나아제 억제를 통한 암 예방 또는 치료용 조성물로 유용하게 사용될 수 있다.

  该专利涉及一种新型Pim激酶抑制剂及其用途，更详细地说是基于具有Pim激酶抑制活性的新型1,3,4-噁二唑-2(3H)-硫酮(1,3,4-Oxadiazole-2(3H)-thione)化合物和包含该化合物的Pim激酶抑制剂组合物或用于癌症预防或治疗的组合物。由于发现该专利的1,3,4-噁二唑-2(3H)-硫酮(1,3,4-Oxadiazole-2(3H)-thione)基础化合物即使在低浓度下也具有非常有效的Pim激酶抑制活性，因此该专利的化合物可用于作为通过Pim激酶抑制进行癌症预防或治疗的组合物。
• Anti-Inflammatory Effects of the Novel PIM Kinase Inhibitor KMU-470 in RAW 264.7 Cells through the TLR4-NF-κB-NLRP3 Pathway
  作者：Hye Suk Baek、Hyeon Ji Min、Victor Sukbong Hong、Taeg Kyu Kwon、Jong Wook Park、Jinho Lee、Shin Kim

  DOI：10.3390/ijms21145138

  日期：——

  PIM kinases, a small family of serine/threonine kinases, are important intermediates in the cytokine signaling pathway of inflammatory disease. In this study, we investigated whether the novel PIM kinase inhibitor KMU-470, a derivative of indolin-2-one, inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 cells. We demonstrated that KMU-470 suppressed the production of nitric oxide and inducible nitric oxide synthases that are induced by LPS in RAW 264.7 cells. Furthermore, KMU-470 inhibited LPS-induced up-regulation of TLR4 and MyD88, as well as the phosphorylation of IκB kinase and NF-κB in RAW 264.7 cells. Additionally, KMU-470 suppressed LPS-induced up-regulation at the transcriptional level of various pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. Notably, KMU-470 inhibited LPS-induced up-regulation of a major component of the inflammasome complex, NLRP3, in RAW 264.7 cells. Importantly, PIM-1 siRNA transfection attenuated up-regulation of NLRP3 and pro-IL-1β in LPS-treated RAW 264.7 cells. Taken together, these findings indicate that PIM-1 plays a key role in inflammatory signaling and that KMU-470 is a potential anti-inflammatory agent.

  PIM激酶是一类重要的丝氨酸/苏氨酸激酶，在炎症性疾病的细胞因子信号通路中起着重要的中间作用。本研究探讨了一种新型PIM激酶抑制剂KMU-470（indolin-2-one的衍生物）是否能够抑制RAW 264.7细胞中脂多糖（LPS）诱导的炎症反应。我们证明KMU-470能够抑制RAW 264.7细胞中LPS诱导的一氧化氮和诱导型一氧化氮合酶的产生。此外，KMU-470还抑制了RAW 264.7细胞中LPS诱导的TLR4和MyD88的上调，以及IκB激酶和NF-κB的磷酸化。此外，KMU-470还抑制了LPS诱导的多种促炎细胞因子，如IL-1β、TNF-α和IL-6的转录水平上调。值得注意的是，KMU-470还抑制了RAW 264.7细胞中炎症小体复合物的主要成分NLRP3的上调。重要的是，PIM-1 siRNA转染减弱了LPS处理的RAW 264.7细胞中NLRP3和前IL-1β的上调。综上所述，这些发现表明PIM-1在炎症信号传导中起着关键作用，而KMU-470是一种潜在的抗炎药物。