(S,E)-ethyl 4-(tert-butoxycarbonylamino)-7-oxo-7-(tritylamino)-hept-2-enoate | 199005-58-8

• 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: (S,E)-ethyl 4-(tert-butoxycarbonylamino)-7-oxo-7-(tritylamino)-hept-2-enoate
• 英文别名: (S,E)-ethyl 4-(tert-butoxycarbonylamino)-7-oxo-7-(tritylamino)hept-2-enoate；ethyl (E,4S)-4-[(2-methylpropan-2-yl)oxycarbonylamino]-7-oxo-7-(tritylamino)hept-2-enoate
• CAS: 199005-58-8
• 化学式: C₃₃H₃₈N₂O₅
• 分子量: 542.675
• InChiKey: BXXKSYCPDCBGPI-WPJHKJGHSA-N

物化性质

• 熔点：
  147-150 °C
• 沸点：
  732.7±60.0 °C(Predicted)
• 密度：
  1.131±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  40
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  93.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S,E)-ethyl 4-(tert-butoxycarbonylamino)-7-oxo-7-(tritylamino)-hept-2-enoate 在 N-甲基吗啉 、 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 27.5h， 生成 tert-butyl N-[(E,4S)-1-indol-1-yl-1,7-dioxo-7-(tritylamino)hept-2-en-4-yl]carbamate
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 1. Michael Acceptor Structure−Activity Studies

  摘要：

  The structure-based design, chemical synthesis, and biological evaluation of peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds incorporate various Michael acceptor moieties and are shown to irreversibly bind to HRV serotype 14 3CP with inhibition activities (k(obs)/[I]) ranging from 100 to 600 000 M-1 s(-1). These inhibitors are also shown to exhibit antiviral activity when tested against HRV-14-infected H1-HeLa cells with EC50's approaching 0.50 mu M. Extensive structure-activity relationships developed by Michael acceptor alteration are reported along with the evaluation of several compounds against HRV serotypes other than 14. A 2.0 Angstrom crystal structure of a peptide-derived inhibitor complexed with HRV-2 3CP is also detailed.

  DOI：

  10.1021/jm980068d
• 作为产物：
  描述：

  N-Boc-N'-三苯甲基-L-谷氨酰胺 在 N-甲基吗啉 、 lithium aluminium tetrahydride 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 30.0h， 生成 (S,E)-ethyl 4-(tert-butoxycarbonylamino)-7-oxo-7-(tritylamino)-hept-2-enoate
  参考文献：
  名称：

  谷氨酰胺乙烯基酯蛋白酶体抑制剂对胰蛋白酶样（beta2）亚基具有选择性。

  摘要：

  在这里，我们报告了一系列新的基于肽的蛋白酶体抑制剂的研究，这些抑制剂在C端带有乙烯基酯部分。在某些衍生物的中心部分，苯丙氨酸的刚性类似物Tic的存在不利于该活性。该系列的最佳类似物显示出对β2亚基的有效和选择性抑制作用，并具有良好的酶稳定性。

  DOI：

  10.1016/j.ejmech.2006.12.008

文献信息

• Michael Acceptor Based Antiplasmodial and Antitrypanosomal Cysteine Protease Inhibitors with Unusual Amino Acids
  作者：Alexander Breuning、Björn Degel、Franziska Schulz、Christian Büchold、Martin Stempka、Uwe Machon、Saskia Heppner、Christoph Gelhaus、Matthias Leippe、Matthias Leyh、Caroline Kisker、Jennifer Rath、August Stich、Jiri Gut、Philip J. Rosenthal、Carsten Schmuck、Tanja Schirmeister

  DOI：10.1021/jm900946n

  日期：2010.3.11

  New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The Compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing Compounds, the maleic acid derivatives 42 and 43 (BnO-Phe <- Mal-Phe-OBn, BnO-Phe <- Mal-Phe-Ala-OBn. Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe <- Fum-Phe-OBn) only displayed inhibition or the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.
• Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 2. Peptide Structure−Activity Studies
  作者：Peter S. Dragovich、Stephen E. Webber、Robert E. Babine、Shella A. Fuhrman、Amy K. Patick、David A. Matthews、Siegfried H. Reich、Joseph T. Marakovits、Thomas J. Prins、Ru Zhou、Jayashree Tikhe、Ethel S. Littlefield、Ted M. Bleckman、Michael B. Wallace、Thomas L. Little、Clifford E. Ford、James W. Meador、Rose Ann Ferre、Edward L. Brown、Susan L. Binford、Dorothy M. DeLisle、Stephen T. Worland

  DOI：10.1021/jm9800696

  日期：1998.7.1

  The structure-based design, chemical synthesis, and biological evaluation of various peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (k(obs)/[I]) ranging from 60 to 280 000 M-1 s(-1) and antiviral EC50's which approach 0.15 mu M. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (k(obs)/[I] = 800 000 M-1 s(-1)) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 mu M). A 1.9 Angstrom crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-8 3CP is also detailed.
• Solid-phase synthesis of irreversible human rhinovirus 3C protease inhibitors. Part 1: Optimization of tripeptides incorporating N-terminal amides
  作者：P Dragovich

  DOI：10.1016/s0968-0896(99)00005-x

  日期：1999.4

  The optimization of a series of irreversible human rhinovirus (HRV) 3C protease (3CP) inhibitors is described. These inhibitors are comprised of an L-Leu-L-Phe-L-Gln tripeptide containing an N-terminal amide moiety and a C-terminal ethyl propenoate Michael acceptor. Examination of approximately 500 compounds with varying N-terminal amides utilizing solid-phase synthesis and high-throughput assay techniques is described along with the solution phase preparation of several highly active molecules. A tripeptide Michael acceptor containing an N-terminal amide derived from 5-methylisoxazole-3-carboxylic acid is shown to exhibit potent, irreversible anti-3CP activity (k(obs)/[I] = 260,000 M-1 s(-1); type-14 3CP) and broad-spectrum antirhinoviral properties (average EC50 = 0.47 mu M against four different HRV serotypes). (C) 1999 Elsevier Science Ltd. All rights reserved.
• Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids
  作者：Peter S Dragovich、Stephen E Webber、Thomas J Prins、Ru Zhou、Joseph T Marakovits、Jayashree G Tikhe、Shella A Fuhrman、Amy K Patick、David A Matthews、Clifford E Ford、Edward L Brown、Susan L Binford、James W Meador、Rose Ann Ferre、Stephen T Worland

  DOI：10.1016/s0960-894x(99)00368-6

  日期：1999.8

  Tripeptide-derived molecules incorporating N-methyl amino acid residues and C-terminal Michael acceptor moieties were evaluated as irreversible inhibitors of the cysteine-containing human rhinovirus 3C protease (3CP). Such compounds displayed good 3CP inhibition activity (k(obs)/[I] up to 610,000 M(-1)s(-1)) and potent in vitro antiviral properties (EC50 approaching 0.03 mu M) when tested against HRV serotype-14. (C) 1999 Elsevier Science Ltd. All rights reserved.
• Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. Part 7: Structure–Activity Studies of Bicyclic 2-Pyridone-Containing Peptidomimetics
  作者：Peter S. Dragovich、Thomas J. Prins、Ru Zhou、Theodore O. Johnson、Edward L. Brown、Fausto C. Maldonado、Shella A. Fuhrman、Leora S. Zalman、Amy K. Patick、David A. Matthews、Xinjun Hou、James W. Meador、Rose Ann Ferre、Stephen T. Worland

  DOI：10.1016/s0960-894x(02)00008-2

  日期：2002.3

  The structure-based design, chemical synthesis. and biological evaluation of bicyclic 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. An optimized compound is shown to exhibit antiviral activity when tested against a variety of HRV serotypes (EC50's ranging from 0.037 to 0.162 muM). (C) 2002 Elsevier Science Ltd. All rights reserved.