N-(tert-butyloxycarbonyl)-L-glutamic acid α-benzyl ester γ-tert-butylamide | 102651-05-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(tert-butyloxycarbonyl)-L-glutamic acid α-benzyl ester γ-tert-butylamide
• 英文别名: (S)-benzyl 2-(tert-butoxycarbonylamino)-5-(tert-butylamino)-5-oxopentanoate；benzyl (2S)-5-(tert-butylamino)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoate
• CAS: 102651-05-8
• 化学式: C₂₁H₃₂N₂O₅
• 分子量: 392.495
• InChiKey: WTICZXRPSPGHMF-INIZCTEOSA-N

物化性质

• 沸点：
  568.3±50.0 °C(Predicted)
• 密度：
  1.093±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.32
• 重原子数：
  28.0
• 可旋转键数：
  7.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  93.73
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  N-(tert-butyloxycarbonyl)-L-glutamic acid α-benzyl ester γ-tert-butylamide 在 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 (S)-(3-((2-(2-(1H-indol-3-yl)-2-oxoacetamido)-5-(tert-butylamino)-5-oxopentanamido)methyl)phenyl)boronic acid
  参考文献：
  名称：

  人类组成型蛋白酶体 β5c 胰凝乳蛋白酶亚基的高选择性抑制剂的发现

  摘要：

  我们描述了我们对人类组成型蛋白酶体胰凝乳蛋白酶活性 (β5c) 的有效且高选择性抑制剂的发现和开发。新型抑制剂的构效关系研究重点是化学基团天冬酰胺的N帽、 C帽和侧链的优化。化合物32是本研究中最有效、最具选择性的 β5c 抑制剂。对接研究为效力和选择性提供了结构原理。动力学研究显示了可逆且非竞争性的抑制机制。它进入细胞与蛋白酶体靶标结合，通过与 β5i 选择性抑制剂协同作用，有效选择性地杀死多发性骨髓瘤细胞。

  DOI：

  10.1021/acs.jmedchem.2c00733
• 作为产物：
  描述：

  N-叔丁氧羰基-L-谷氨酸 1-苄酯 、 叔丁胺 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以93 %的产率得到N-(tert-butyloxycarbonyl)-L-glutamic acid α-benzyl ester γ-tert-butylamide
  参考文献：
  名称：

  人类组成型蛋白酶体 β5c 胰凝乳蛋白酶亚基的高选择性抑制剂的发现

  摘要：

  我们描述了我们对人类组成型蛋白酶体胰凝乳蛋白酶活性 (β5c) 的有效且高选择性抑制剂的发现和开发。新型抑制剂的构效关系研究重点是化学基团天冬酰胺的N帽、 C帽和侧链的优化。化合物32是本研究中最有效、最具选择性的 β5c 抑制剂。对接研究为效力和选择性提供了结构原理。动力学研究显示了可逆且非竞争性的抑制机制。它进入细胞与蛋白酶体靶标结合，通过与 β5i 选择性抑制剂协同作用，有效选择性地杀死多发性骨髓瘤细胞。

  DOI：

  10.1021/acs.jmedchem.2c00733

文献信息

• 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。
• Structure–Activity Relationships of Noncovalent Immunoproteasome β5i-Selective Dipeptides
  作者：Wenhu Zhan、Pradeep K. Singh、Yi Ban、Xiaoping Qing、Marie Dominique Ah Kioon、Hao Fan、Quanju Zhao、Rong Wang、George Sukenick、Jane Salmon、J. David Warren、Xiaojing Ma、Franck J. Barrat、Carl F. Nathan、Gang Lin

  DOI：10.1021/acs.jmedchem.0c01520

  日期：2020.11.12

  relationship study of a class of noncovalent proteasome inhibitors with picomolar potencies and 1000-fold selectivity for i-20S over c-20S. Furthermore, these inhibitors are specific for β5i over the other five active subunits of i-20S and c-20S, providing useful tools to study the functions of β5i in immune responses. The potency of these compounds in inhibiting human T cell activation suggests that they

  免疫蛋白酶体 (i-20S) 已成为自身免疫和炎症性疾病以及血液系统恶性肿瘤的治疗靶点。抑制 i-20S 的糜蛋白酶 β5i 亚基可在体外抑制 T 细胞活化、B 细胞增殖和树突状细胞分化，并抑制自身免疫性疾病和同种异体移植物排斥动物模型中的免疫反应。然而，对免疫细胞的细胞毒性伴随着共价反应性 β5i 抑制剂的使用，其对组成型蛋白酶体 (c-20S) 的活性随着暴露时间而累积。在此，我们报告了一类非共价蛋白酶体抑制剂的结构-活性关系研究，这些抑制剂具有皮摩尔效力，对 i-20S 的选择性比 c-20S 高 1000 倍。此外，这些抑制剂对 β5i 的特异性优于 i-20S 和 c-20S 的其他五个活性亚基，为研究 β5i 在免疫反应中的功能提供了有用的工具。这些化合物在抑制人类 T 细胞活化方面的效力表明它们可能具有治疗潜力。
• DIPEPTIDES AS INHIBITORS OF HUMAN IMMUNOPROTEASOMES
  申请人：CORNELL UNIVERSITY

  公开号：US20170121366A1

  公开（公告）日：2017-05-04

  The compounds of the present invention are represented by the following compounds having Formula (I) where the substituents R 1 -R 10 , X, Y, k, m, n, q, and s are as defined herein. These compounds are used in the treatment of cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders or for providing immunosuppression for transplanted organs or tissues.

  本发明的化合物由以下具有式（I）的化合物表示，其中取代基R1-R10、X、Y、k、m、n、q和s的定义如本文所述。这些化合物用于治疗癌症、免疫紊乱、自身免疫性疾病、神经退行性疾病或炎症性疾病，或用于为移植的器官或组织提供免疫抑制。
• Identification of N, C-capped di- and tripeptides as selective immunoproteasome inhibitors
  作者：Guanglei Nan、Lei Huang、Yunxuan Li、Yajun Yang、Ying Yang、Ke Li、Fangfang Lai、Xiaoguang Chen、Zhiyan Xiao

  DOI：10.1016/j.ejmech.2022.114252

  日期：2022.4

  showed an IC50 of 0.94 nM. A selective β5i inhibitor (54) with over 500-fold β5i/β5c selectivity was identified. Three of the inhibitors were found to selectively inhibit β5i and β5c, and showed no noticeable inhibition against the other four subunits. Six inhibitors with significant inhibitory activity against the HCT-116 cells were recognized, and the most active inhibitors, 14 and 50, showed IC50 values

  基于已知的抑制剂4-CA设计了一系列 N、C 封端的二肽和三肽作为选择性免疫蛋白酶体抑制剂。合成并评价了 48 种新化合物，并探索了该类化合物作为 β5i 选择性抑制剂的构效关系 (SAR)。大多数这些化合物对免疫蛋白酶体的 β5i 亚基显示出显着的抑制作用，最有效的 β5i 抑制剂 ( 15 ) 显示出 0.94 nM 的 IC 50。一种选择性 β5i 抑制剂（54) 具有超过 500 倍的 β5i/β5c 选择性。发现其中三种抑制剂选择性地抑制β5i和β5c，并且对其他四种亚基没有明显的抑制作用。识别出六种对 HCT-116 细胞具有显着抑制活性的抑制剂，最有效的抑制剂14和50的 IC 50值分别为 0.46 μM 和 0.16 μM。一些选择性β5i抑制剂对细胞因子TNF-α和IL-6的释放表现出显着的抑制作用。该结果不仅为阐明亚基选择性与药理学特征之间的关系提供了有效的化学工具
• Methotrexate analogs. 28. Synthesis and biological evaluation of new .gamma.-monoamides of aminopterin and methotrexate
  作者：Andre Rosowsky、Henry Bader、Mary Radike-Smith、Carol A. Cucchi、Michael M. Wick、James H. Freisheim

  DOI：10.1021/jm00159a023

  日期：1986.9

  Lipophilic gamma-monoamide derivatives of aminopterin (AMT) were synthesized in high overall yield from 4-amino-4-deoxy-N10-formylpteroic acid and gamma-N-tert-alkyl-, gamma-N-aralkyl-, or gamma-N-arylamides of alpha-benzyl L-glutamate via a modification of the mixed carboxylic-carbonic anhydride coupling method. Coupling was also accomplished with p-nitrophenyl 4-amino-4-deoxy-N10-formylpteroate. Compounds obtained in this manner included the gamma-tert-butylamide, gamma-(1-adamantylamide), gamma-benzylamide, gamma-(3,4-dichlorobenzylamide), gamma-(2,6-dichlorobenzylamide), gamma-anilide, gamma-(3,4-methylenedioxyanilide), and gamma-(3,4-dihydroxanilide) derivatives of AMT. Also prepared, from 4-amino-4-deoxy-N10-methylpteroic acid via diethyl phosphorocyanidate coupling, was the gamma-(3,4-methylenedioxyanilide) of MTX. The methylenedioxyanilides were cleaved smoothly to dihydroxyanilides with boron tris(trifluoroacetate) in trifluoroacetic acid. All the gamma-monoamides were tested as inhibitors of purified dihydrofolate reductase (DHFR) from murine L1210 leukemia cells and as inhibitors of the growth of wild-type L1210 cells and a subline (L1210/R81) with high-level resistance to MTX and AMT based mainly on a defect in drug uptake via active transport. Several compounds were also tested against human leukemic lymphoblasts (CEM cells) and a resistant subline (CEM/MTX) whose resistance is likewise based on uptake. The IC50 of the gamma-monoamides against DHFR was 1.5- to 5-fold higher than that of the parent acids, but the IC50 against cultured cells varied over a much broader range, suggesting that uptake and/or metabolism rather than DHFR binding are principal determinants of in vitro growth inhibitory activity for these compounds. gamma-N-Aryl and gamma-N-aralkyl derivatives appeared to be more potent than gamma-N-tert-alkyl derivatives. Where comparison could be made, AMT gamma-monoamides were more potent than MTX gamma-monoamides. Several of the gamma-monoamides showed potency comparable to that of the parent acid against wild-type L1210 and CEM cells; all of them were more potent than MTX against the L1210/R81 subline; and some of the AMT gamma-monoamides were also more potent than the parent acid against resistant CEM/MTX cells. As a group, however, the gamma-monoamides were considerably more active against the murine cells than against the human cells, suggesting that the former may take up the amides better or may be able to metabolize them more efficiently than the parent acids. All the gamma-monoamides were tested in vivo against L1210 leukemia in mice.(ABSTRACT TRUNCATED AT 400 WORDS)