tert-butyl 4-(thiazol-2-ylcarbamoyl)piperidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 4-(thiazol-2-ylcarbamoyl)piperidine-1-carboxylate
• 英文别名: Tert-butyl 4-(1,3-thiazol-2-ylcarbamoyl)piperidine-1-carboxylate
• 化学式: C₁₄H₂₁N₃O₃S
• mdl: MFCD10641242
• 分子量: 311.405
• InChiKey: HRPXFLYETFUYQM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.642
• 拓扑面积：
  99.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(thiazol-2-ylcarbamoyl)piperidine-1-carboxylate 在 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 3.0h， 生成
  参考文献：
  名称：

  开发肽环氧基酮作为选择性免疫蛋白酶体抑制剂

  摘要：

  设计、合成和评估了一系列具有不同N帽和 P3 构型的环氧酮类似物。我们发现P3中的D -Ala 对于β 5i 选择性超过β 5c至关重要。值得注意的是，在 P3 具有D-构型的化合物20j（β 5i IC 50  = 26.0 nM，25 倍选择性）和20l（β 5i IC 50 = 25.1 nM，24 倍选择性）是最具选择性的抑制剂。虽然20j和20l仅对 RPMI-8226 和 MM.1S 细胞系显示出中等的抗增殖活性，根据我们的实验，这表明单独抑制β 5i 不足以发挥抗癌作用，可能依赖于β 1i的互补抑制，β 5c 和β 5i。这些数据进一步增加了我们对血液系统恶性肿瘤中免疫蛋白酶体抑制剂的理解。

  DOI：

  10.1016/j.ejmech.2021.113556
• 作为产物：
  描述：

  1-Boc-4-哌啶甲酸 在 吡啶 、 4-二甲氨基吡啶 、 氯化亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 tert-butyl 4-(thiazol-2-ylcarbamoyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors

  摘要：

  A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4 +/- 0.1 nM) and cytotoxicities with IC50 values at 13.9 +/- 1.8 nM and 9.5 +/- 0.5 nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27-29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.10.002

文献信息

• Exploration of novel piperazine or piperidine constructed non-covalent peptidyl derivatives as proteasome inhibitors
  作者：Rangxiao Zhuang、Lixin Gao、Xiaoqing Lv、Jianjun Xi、Li Sheng、Yanmei Zhao、Ruoyu He、Xiaobei Hu、Yidan Shao、Xuwang Pan、Shourong Liu、Weiwei Huang、Yubo Zhou、Jia Li、Jiankang Zhang

  DOI：10.1016/j.ejmech.2016.12.034

  日期：2017.1

  A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC50 values lower than 10 nM. Subsequently

  设计，合成和评价了一系列具有新戊基-天冬酰胺残基的新的哌嗪或含哌啶的非共价肽基衍生物，并评价它们为蛋白酶体抑制剂。筛选了所有目标化合物的20S蛋白酶体胰凝乳蛋白酶样抑制活性，其中15种化合物比卡非佐米具有更强的活性，IC 50值低于10 nM。随后，测试了最有效的10种类似物对两种多发性骨髓瘤（MM）细胞系RPMI-8226和MM-1S的细胞毒活性。基于这些实验，进一步评估了所选衍生物的离体和体内血细胞蛋白酶体抑制活性。最有潜力的化合物35（蛋白酶体抑制IC 50：1.2±0.1 nM），具有有效的抗增殖作用（IC 50：RPMI-8226 8.4±0.8 nM； MM-1S：6.3±0.8 nM），离体和体内活性也具有延长的半衰期在血浆中的抗性，这表明通过在肽骨架中构建六元环可提高该系列化合物的酶稳定性。所有的实验都证实了设计概念的正确性，这使得该系列化合物成为探索新的抗MM药物的潜在线索。
• Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles
  作者：Xiao-Wu Dong、Jian-Kang Zhang、Lei Xu、Jin-Xin Che、Gang Cheng、Xiao-Bei Hu、Li Sheng、An-Hui Gao、Jia Li、Tao Liu、Yong-Zhou Hu、Yu-Bo Zhou

  DOI：10.1016/j.ejmech.2018.12.064

  日期：2019.2

  The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the 55 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Development of peptide epoxyketones as selective immunoproteasome inhibitors
  作者：Xuemei Li、Duidui Hong、Mengmeng Zhang、Lei Xu、Yubo Zhou、Jia Li、Tao Liu

  DOI：10.1016/j.ejmech.2021.113556

  日期：2021.10

  crucial for β5i selectivity over β5c. Notably, compounds 20j (β5i IC50 = 26.0 nM, 25-fold selectivity) and 20l (β5i IC50 = 25.1 nM, 24-fold selectivity) with the D-configuration at P3 were the most selective inhibitors. Although 20j and 20l showed only moderate anti-proliferative activity against RPMI-8226 and MM.1S cell lines, based on our experiments, it indicates that the inhibition of β5i alone is

  设计、合成和评估了一系列具有不同N帽和 P3 构型的环氧酮类似物。我们发现P3中的D -Ala 对于β 5i 选择性超过β 5c至关重要。值得注意的是，在 P3 具有D-构型的化合物20j（β 5i IC 50  = 26.0 nM，25 倍选择性）和20l（β 5i IC 50 = 25.1 nM，24 倍选择性）是最具选择性的抑制剂。虽然20j和20l仅对 RPMI-8226 和 MM.1S 细胞系显示出中等的抗增殖活性，根据我们的实验，这表明单独抑制β 5i 不足以发挥抗癌作用，可能依赖于β 1i的互补抑制，β 5c 和β 5i。这些数据进一步增加了我们对血液系统恶性肿瘤中免疫蛋白酶体抑制剂的理解。
• Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors
  作者：Jiankang Zhang、Lixin Gao、Jianjun Xi、Li Sheng、Yanmei Zhao、Lei Xu、Yidan Shao、Shourong Liu、Rangxiao Zhuang、Yubo Zhou、Jia Li

  DOI：10.1016/j.bmc.2016.10.002

  日期：2016.12

  A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4 +/- 0.1 nM) and cytotoxicities with IC50 values at 13.9 +/- 1.8 nM and 9.5 +/- 0.5 nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27-29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs. (C) 2016 Elsevier Ltd. All rights reserved.