tert-butyl 4-(4-fluorophenylcarbamoyl) piperidine-1-carboxylate | 503149-31-3

• 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-(4-fluorophenylcarbamoyl) piperidine-1-carboxylate
• 英文别名: Tert-butyl 4-[(4-fluorophenyl)carbamoyl]piperidine-1-carboxylate
• CAS: 503149-31-3
• 化学式: C₁₇H₂₃FN₂O₃
• 分子量: 322.38
• InChiKey: ZLNAJCWEUVFTBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(4-fluorophenylcarbamoyl) piperidine-1-carboxylate 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 4-(4-fluorophenylcarbamoyl)piperidine-1-carbonyl-hPhe-hPhe-2-chlorobenzylamide
  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
• 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-(4-fluorophenylcarbamoyl) 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。
• Optimization of piperidine constructed peptidyl derivatives as proteasome inhibitors
  作者：Yanmei Zhao、Lei Xu、Jiankang Zhang、Mengmeng Zhang、Jingyi Lu、Ruoyu He、Jianjun Xi、Rangxiao Zhuang、Jia Li、Yubo Zhou

  DOI：10.1016/j.bmc.2020.115867

  日期：2021.1

  A series of non-covalent piperidine-containing peptidyl derivatives with various substituents at side chains of different residues were designed, synthesized and evaluated as proteasome inhibitors. After proteasome inhibitory evaluations of all the synthesized target compounds, selected ones were tested for their anti-proliferation activities against three multiple myeloma (MM) cell lines. 8 analogues

  一系列在不同残基的侧链上具有各种取代基的非共价含哌啶肽基衍生物被设计、合成并评估为蛋白酶体抑制剂。在对所有合成的目标化合物进行蛋白酶体抑制评估后，测试所选化合物对三种多发性骨髓瘤 (MM) 细胞系的抗增殖活性。8 种类似物显示出比卡非佐米更有效的活性，最有前途的化合物24对 20S 蛋白酶体的IC 50值为 0.8±0.2 nM，对RPMI 82926 的IC 50值为 8.42±0.74 nM、7.14±0.52 nM、14.20±1.08 nM MM.1S 细胞系，分别。此外，代表性化合物24的抗癌活性机制被进一步调查。RPMI-8226 细胞的凋亡是通过积累多聚泛素和诱导 caspase 和 PARP 的裂解来实现的。此外，优化后化合物24在大鼠血浆中的半衰期延长，这将有助于提高该系列衍生物的体内活性。所有研究证实，含哌啶的非共价蛋白酶体抑制剂可能是抗 MM 药物开发的潜在线索。
• Design, synthesis and biological evaluation of novel diazaspirodecanone derivatives containing piperidine-4-carboxamide as chitin synthase inhibitors and antifungal agents
  作者：Qinggang Ji、Bing Li、Yiwen Chu、Hu Wu、Chuanbiao Du、Yajie Xu、Yangli Shen、Junfeng Deng

  DOI：10.1016/j.bioorg.2021.105108

  日期：2021.9

  A series of novel 2-oxo-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)ethylpiperidine carboxamide derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS spectroscopy. All eighteen newly prepared compounds were evaluated for their inhibition against chitin synthase (CHS) and antifungal activities in vitro. The enzyme assay revealed that compound 5h showed excellent inhibitory activity

  设计、合成了一系列新型2-oxo-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)乙基哌啶甲酰胺衍生物，并通过1 H NMR、13 C NMR和HRMS光谱对其进行了表征。评估了所有 18 种新制备的化合物对几丁质合成酶 (CHS) 的抑制作用和体外抗真菌活性。酶法分析表明，化合物5h对CHS显示出优异的抑制活性，IC 50值为0.10 mM，化合物5b、5d和5q对几丁质合酶显示出良好的抑制作用，IC 50值分别为0.13 mM、0.18 mM和0.15 mM , 而 IC 50ployoxin B 的值为 0.08 mM。同时，这些化合物中的其他化合物对几丁质合酶表现出中等的抑制效力。抗真菌试验表明，与对照药物氟康唑和多氧菌素 B 相比，化合物5h对这些测试菌株（包括白色念珠菌、烟曲霉、新型念珠菌和黄曲霉）具有优异的抗真菌活性。其优异的抗真菌活性与其优异的几
• EP1426366
  申请人：——

  公开号：——

  公开（公告）日：——
• 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.