(9H-fluoren-9-yl)methyl (S)-(1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl)propan-2-yl)carbamate | 170852-98-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (9H-fluoren-9-yl)methyl (S)-(1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl)propan-2-yl)carbamate
• 英文别名: Fmoc-His(Trt)-N(OMe)Me；9H-fluoren-9-ylmethyl N-[(2S)-1-[methoxy(methyl)amino]-1-oxo-3-(1-tritylimidazol-4-yl)propan-2-yl]carbamate
• CAS: 170852-98-9
• 化学式: C₄₂H₃₈N₄O₄
• 分子量: 662.788
• InChiKey: GQUFFCJNDAXMCP-KDXMTYKHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.19
• 重原子数：
  50.0
• 可旋转键数：
  11.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  85.69
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (9H-fluoren-9-yl)methyl (S)-(1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl)propan-2-yl)carbamate 在 叔丁胺 作用下， 以 二氯甲烷 为溶剂， 生成 H-His(Trt)-N(OMe)Me
  参考文献：
  名称：

  基于组氨酸的强效抗疟药

  摘要：

  合成了一类新型组氨酸抗疟药的几种类似物。其中，化合物8g、8h和15表现出优异的抗疟活性。对接研究表明，这些抗疟药与其结合位点强烈相互作用。在表型测定中，发现化合物8 g抑制了寄生虫食物液泡中的血红蛋白降解。

  DOI：

  10.1002/cmdc.202200709
• 作为产物：
  描述：

  N-Fmoc-N'-三苯甲基-L-组氨酸 在 二甲羟胺盐酸盐 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 以98%的产率得到(9H-fluoren-9-yl)methyl (S)-(1-(methoxy(methyl)amino)-1-oxo-3-(1-trityl-1H-imidazol-4-yl)propan-2-yl)carbamate
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Evaluation of Peptide-Mimetic SARS 3CL Protease Inhibitors

  摘要：

  The design and evaluation of low molecular weight peptide-based severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL) protease inhibitors are described. A substrate-based peptide aldehyde was selected as a starting compound, and optimum side-chain structures were determined, based on a comparison of inhibitory activities with Michael type inhibitors. For the efficient screening of peptide aldehydes containing a specific C-terminal residue, a new approach employing thioacetal to aldehyde conversion mediated by N-bromosuccinimide was devised. Structural optimization was carried out based on X-ray crystallographic analyses of the R1881 SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC50 value of 98 nM. The resulting compound carried no substrate sequence, except for a P-3 site directed toward the outside of the protease. X-ray crystallography provided insights into the protein-ligand interactions.

  DOI：

  10.1021/jm200870n

文献信息

• 1,2,3-Triazoles as Amide Bond Mimics: Triazole Scan Yields Protease-Resistant Peptidomimetics for Tumor Targeting
  作者：Ibai E. Valverde、Andreas Bauman、Christiane A. Kluba、Sandra Vomstein、Martin A. Walter、Thomas L. Mindt

  DOI：10.1002/anie.201303108

  日期：2013.8.19

  The triazole makes the difference: Replacement of amide bonds in the backbone of peptides by 1,4‐disubstituted 1,2,3‐triazole isosteres affords peptidomimetics with retained receptor affinity and cell‐internalization properties, enhanced proteolytic stability, and improved tumor‐targeting capabilities.

  三唑的作用与众不同：用1,4-二取代的1,2,3-三唑等位基因取代肽主链中的酰胺键可提供拟肽，具有保留的受体亲和力和细胞内在化特性，增强了蛋白水解的稳定性，并改善了肿瘤靶向性能力。
• Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor
  作者：Kouji Ohnishi、Yasunao Hattori、Kazuya Kobayashi、Kenichi Akaji

  DOI：10.1016/j.bmc.2018.12.019

  日期：2019.1

  for the moderate inhibitory activity. In this study, the effects of an additional non-prime site substituent on the scaffold as well as effects of several warheads are evaluated. For the introduction of a desired non-prime site substituent, amino functionality was introduced on the decahydroisoquinolin scaffold, and the scaffold was constructed by Pd(II) catalyzed diastereoselective ring formation.

  非主要位点取代基和弹头与十氢异喹啉支架组合被评估为严重急性呼吸综合征 (SARS) 糜蛋白酶样蛋白酶 (3CL pro ) 的新型抑制剂。十氢异喹啉支架已被证明是与 SARS 3CL pro的 S2 位点相互作用的有效疏水中心，但 S3 到 S4 位点缺乏相互作用被认为是中度抑制活性的主要原因。在这项研究中，评估了额外的非主要位点取代基对支架的影响以及几个弹头的影响。为了引入所需的非主要位点取代基，在十氢异喹啉支架上引入氨基官能团，并通过 Pd(II) 催化的非对映选择性环形成来构建支架。合成的十氢异喹啉抑制剂与非主要位点取代基结合时，对 SARS 3CL pro的抑制活性约为 2.4 倍。目前的结果不仅表明与 SARS 3CL pro的预期额外相互作用但也有可能使用含有稠环系统作为疏水支架和新弹头（如硫缩醛）的新抑制剂。
• Incorporation of a Bioactive Reverse-Turn Heterocycle into a Peptide Template Using Solid-Phase Synthesis To Probe Melanocortin Receptor Selectivity and Ligand Conformations by 2D ¹H NMR
  作者：Anamika Singh、Andrzej Wilczynski、Jerry R. Holder、Rachel M. Witek、Marvin L. Dirain、Zhimin Xiang、Arthur S. Edison、Carrie Haskell-Luevano

  DOI：10.1021/jm101425m

  日期：2011.3.10

  the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nanomolar potency. Biophysical structural analysis [2D 1H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small

  通过使用固相合成方法，将具有生物活性的反向转向杂环并入环肽模板中，以探测黑皮质素受体效力和配体结构构象。五种黑皮质素受体亚型 (MC1R-MC5R) 是 G 蛋白偶联受体 (GPCR)，受内源性激动剂和拮抗剂调节。该途径涉及色素沉着、体重和能量稳态。在此，我们报告了与小分子部分集成的嵌合 AGRP-黑皮质素肽模板的新型类似物，以使用反向转向杂环来探测核心 His-Phe-Arg-Trp 肽域的结构和功能后果。据报道，一系列六种化合物导致对具有纳摩尔效力的完全激动剂无活性。生物物理结构分析 [2D 1H NMR 和计算机辅助分子建模 (CAMM)] 对选定的类似物进行了研究，结果表明，与参考肽相比，这些肽-小分子杂交体具有更高的灵活性和更少的离散构象家族，并为进一步研究提供了新的模板。结构-功能研究。
• Asymmetric Synthesis of Lysine Analogues with Reduced Basicity, and their Incorporation into Proteasome Inhibitors
  作者：Gerjan de Bruin、Eva J. van Rooden、David Ward、Charlotte Wesseling、Adrianus M. C. H. van den Nieuwendijk、Constant A. A. van Boeckel、Christoph Driessen、Alexei F. Kisselev、Bogdan I. Florea、Mario van der Stelt、Herman S. Overkleeft

  DOI：10.1002/ejoc.201701174

  日期：2017.10.25

  described. These amino acids, as well as histidine and diaminopropionic-acid-glycine, were incorporated at the P1 and/or P3 positions of oligopeptide vinyl sulfones. All inhibitors were found to inhibit proteasome subunit β2, but with a loss of potency compared to our most potent and selective β2 inhibitor, LU-102.

  描述了赖氨酸（4-ene）和赖氨酸（4-yne）的第一次对映选择性合成。这些氨基酸以及组氨酸和二氨基丙酸-甘氨酸被掺入到寡肽乙烯基砜的P1和/或P3位置。发现所有抑制剂均能抑制蛋白酶体亚基β2，但与我们最有效和选择性最强的β2抑制剂LU-102相比，其功效却有所降低。
• Solid-phase synthesis and screening of N-acylated polyamine (NAPA) combinatorial libraries for protein binding
  作者：Jaclyn A. Iera、Lisa M. Miller Jenkins、Hiroshi Kajiyama、Jeffrey B. Kopp、Daniel H. Appella

  DOI：10.1016/j.bmcl.2010.09.054

  日期：2010.11

  Inhibitors for protein-protein interactions are challenging to design, in part due to the unique and complex architectures of each protein's interaction domain. Most approaches to develop inhibitors for these interactions rely on rational design, which requires prior structural knowledge of the target and its ligands. In the absence of structural information, a combinatorial approach may be the best alternative to finding inhibitors of a protein-protein interaction. Current chemical libraries, however, consist mostly of molecules designed to inhibit enzymes. In this manuscript, we report the synthesis and screening of a library based on an N-acylated polyamine (NAPA) scaffold that we designed to have specific molecular features necessary to inhibit protein-protein interactions. Screens of the library identified a member with favorable binding properties to the HIV viral protein R (Vpr), a regulatory protein from HIV, that is involved in numerous interactions with other proteins critical for viral replication. Published by Elsevier Ltd.