tert-butyl [5-(2-cyanoacetyl)-4-methylthiazol-2-yl](methyl)carbamate | 1421693-01-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl [5-(2-cyanoacetyl)-4-methylthiazol-2-yl](methyl)carbamate
• 英文别名: tert-butyl N-[5-(2-cyanoacetyl)-4-methyl-1,3-thiazol-2-yl]-N-methylcarbamate
• CAS: 1421693-01-7
• 化学式: C₁₃H₁₇N₃O₃S
• 分子量: 295.362
• InChiKey: XHSMPAOXHDUOLJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  112
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl [5-(2-cyanoacetyl)-4-methylthiazol-2-yl](methyl)carbamate 以 乙二醇甲醚 为溶剂， 生成 2-[3-(4-Acetylpiperazin-1-yl)anilino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile
  参考文献：
  名称：

  Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

  摘要：

  Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the CS-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B-and T-cells.

  DOI：

  10.1021/jm301475f
• 作为产物：
  描述：

  4-甲基-2-(甲基氨基)-1,3-噻唑-5-甲酸乙酯 在 4-二甲氨基吡啶 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 10.33h， 生成 tert-butyl [5-(2-cyanoacetyl)-4-methylthiazol-2-yl](methyl)carbamate
  参考文献：
  名称：

  Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

  摘要：

  Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the CS-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B-and T-cells.

  DOI：

  10.1021/jm301475f

文献信息

• Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents
  作者：Solomon Tadesse、Laychiluh Bantie、Khamis Tomusange、Mingfeng Yu、Saiful Islam、Nataliya Bykovska、Benjamin Noll、Ge Zhu、Peng Li、Frankie Lam、Malika Kumarasiri、Robert Milne、Shudong Wang

  DOI：10.1111/bph.13974

  日期：2018.6

  D-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle and are actively pursued as therapeutic targets in cancer. We sought to discover a novel series of orally bioavailable and highly selective small molecule inhibitors of CDK4/6. EXPERIMENTAL APPROACH The discovery of pharmacological inhibitors and optimization for potency, selectivity and drug

  背景和目的细胞周期蛋白D依赖性激酶4和6（CDK4 / 6）是细胞周期从G1到S相转变的关键调节剂，并被积极地用作癌症的治疗靶标。我们试图发现一系列新型的口服生物利用度和高选择性的CDK4 / 6小分子抑制剂。实验方法通过迭代化学合成，针对一组激酶的生化筛选，测量细胞生存力，细胞周期分布，诱导细胞凋亡和细胞凋亡水平的基于细胞的测定，实现了药理抑制剂的发现以及药效，选择性和药物性质的优化。视网膜母细胞瘤肿瘤抑制蛋白（Rb）磷酸化和E2因子（E2F）调控的基因表达以及体外生物制药和体内药代动力学分析。关键结果我们发现了几种领先化合物，它们对CDK4 / 6的选择性是CDK家族其他成员的1000倍以上。铅化合物82、91和95通过诱导G1阻滞并伴随S780处Rb的磷酸化和E2F调控的基因表达减少而有效地抑制了癌细胞的生长。通过对369种人类蛋白激酶对CDK4的显着选择性，已鉴定出91种是高效和口
• N-(嘧啶-2-基)香豆素-7-胺衍生物作为蛋白激酶抑制剂的制法和应用
  申请人：中国药科大学

  公开号：CN112010844B

  公开（公告）日：2023-07-25

  本发明公开了一种细胞周期蛋白依赖性激酶抑制剂，包含如通式(I)所述的N‑(嘧啶‑2‑基)香豆素‑7‑胺衍生物。体外药效学试验证明，本发明涉及的化合物对CDK9激酶具有高选择性的抑制作用，可以应用于降低或抑制细胞中的CDK9激酶的活性。本发明还公开了该抑制剂的制备方法以及在CDK家族激酶介导的疾病，特别是过度增殖性疾病、病毒诱导的感染性疾病、心血管疾病的药物中的应用。
• Synthesis, structure–activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents
  作者：Hao Shao、Shenhua Shi、David W. Foley、Frankie Lam、Abdullah Y. Abbas、Xiangrui Liu、Shiliang Huang、Xiangrui Jiang、Nadiah Baharin、Peter M. Fischer、Shudong Wang

  DOI：10.1016/j.ejmech.2013.08.052

  日期：2013.12

  A series of 2,4,5-trisubstituted pyrimidines have been synthesised and characterised, which exhibited potent CDK inhibition and anti-proliferative activities. The structure activity relationship is analysed and a rational for CDK9 selectivity is discussed. Compound 9s, possessing appreciable selectivity for CDK9 over other CDKs, is capable of activating caspase 3, reducing the level of Mcl-1 anti-apoptotic protein, and inducing cancer cell apoptosis. Crown Copyright (C) 2013 Published by Elsevier Masson SAS. All rights reserved.
• Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities
  作者：Hao Shao、Shenhua Shi、Shiliang Huang、Alison J. Hole、Abdullahi Y. Abbas、Sonja Baumli、Xiangrui Liu、Frankie Lam、David W. Foley、Peter M. Fischer、Martin Noble、Jane A. Endicott、Chris Pepper、Shudong Wang

  DOI：10.1021/jm301475f

  日期：2013.2.14

  Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the CS-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B-and T-cells.