H2N-Trp-Ala-OMe | 63430-78-4

• 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: H2N-Trp-Ala-OMe
• 英文别名: methyl (2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]propanoate
• CAS: 63430-78-4
• 化学式: C₁₅H₁₉N₃O₃
• 分子量: 289.334
• InChiKey: XQXDSEKOOAMXDS-CABZTGNLSA-N

物化性质

• 沸点：
  538.0±50.0 °C(Predicted)
• 密度：
  1.252±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  97.2
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  H2N-Trp-Ala-OMe 在 N,N-二异丙基乙胺 、 三氟乙酸 、 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， 反应 16.0h， 生成
  参考文献：
  名称：

  Selective Inhibitors of the Serine Protease Plasmin:  Probing the S3 and S3‘ Subsites Using a Combinatorial Library

  摘要：

  A combinatorial library of 400 serine protease inhibitors with the general structure Cbz-X-aa-Trp-cyclohexanone-Trp-Y-aa-OH has been constructed. The library was synthesized on the solid phase using mix-and-split synthesis, where 20 different amino acids were incorporated at both the X-aa and Y-aa positions. These two positions correspond to the S3 and S3' subsites of the active site. Iterative deconvolution was used to identify hits from the library. The library was screened against four serine proteases: plasmin, kallikrein, thrombin, and trypsin. Seven inhibitors from the library that showed promising activities were resynthesized using solutionphase methods. Four of these compounds were good inhibitors of plasmin with IC50 values in the range of 2.7 - 3.6 mu M. The most potent of these inhibitors showed > 150-fold selectivity for plasmin when compared to the other three serine proteases.

  DOI：

  10.1021/jm050488k
• 作为产物：
  描述：

  N-叔丁氧羰基-L-色氨酸 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.33h， 生成 H2N-Trp-Ala-OMe
  参考文献：
  名称：

  Selective Inhibitors of the Serine Protease Plasmin:  Probing the S3 and S3‘ Subsites Using a Combinatorial Library

  摘要：

  A combinatorial library of 400 serine protease inhibitors with the general structure Cbz-X-aa-Trp-cyclohexanone-Trp-Y-aa-OH has been constructed. The library was synthesized on the solid phase using mix-and-split synthesis, where 20 different amino acids were incorporated at both the X-aa and Y-aa positions. These two positions correspond to the S3 and S3' subsites of the active site. Iterative deconvolution was used to identify hits from the library. The library was screened against four serine proteases: plasmin, kallikrein, thrombin, and trypsin. Seven inhibitors from the library that showed promising activities were resynthesized using solutionphase methods. Four of these compounds were good inhibitors of plasmin with IC50 values in the range of 2.7 - 3.6 mu M. The most potent of these inhibitors showed > 150-fold selectivity for plasmin when compared to the other three serine proteases.

  DOI：

  10.1021/jm050488k

文献信息

• Synthesis and Antioxidant Activity of Peptide-Based Ebselen Analogues
  作者：Kandhan Satheeshkumar、Govindasamy Mugesh

  DOI：10.1002/chem.201003417

  日期：2011.4.18

  corresponding selenol. To understand the antioxidant activity of the peptide‐based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)‐mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN‐scavenging activity of the Phe‐based peptide analogues was found to be comparable to

  合成了一系列基于二肽和三肽的依布硒啉类似物。通过1 H，13 C和77 Se NMR光谱学和质谱技术对化合物进行表征。谷胱甘肽过氧化物酶（GPx）的抗氧化活性已通过使用H 2 O 2，叔丁基氢过氧化物（tBuOOH）和氢过氧化枯烯（Cum-OOH）作为底物，而谷胱甘肽（GSH）作为共底物。尽管所有基于肽的化合物都具有一个与依ebselen相似的硒唑环，但这些化合物的GPx活性高度取决于与硒唑环氮原子相连的肽部分的性质。据观察，在N末端引入苯丙氨酸（Phe）氨基酸残基会降低所有三个过氧化物系统的活性。另一方面，引入脂肪族氨基酸残基如缬氨酸（Val）可大大增强依布硒啉类似物的GPx活性。基于二肽的依布硒啉衍生物催化活性的差异主要归因于这些化合物对谷胱甘肽和过氧化物的反应性的变化。尽管存在Val‐Ala‐CO2 Me部分有助于形成具有催化活性的硒醇物质，即具有Phe-Ile-CO 2的依ebse
• Peptides and peptidoaldehydes as substrates for the Pictet-Spengler reaction
  作者：Karolina Pulka、Marta Slupska、Anna Puszko、Maria Misiak、Marcin Wilczek、Wiktor Kozminski、Aleksandra Misicka

  DOI：10.1002/psc.2516

  日期：2013.7

  The Pictet–Spengler (PS) reaction was performed with various types of substrates: H‐Trp‐OMe and dipeptides with N‐terminal Trp as arylethylamine components and Z‐protected amino aldehydes and peptidoaldehydes as carbonyl components. We found that the C‐terminal part of Trp derivatives did not have any influence on the stereoselectivity of the reaction and the results are the same for simple esters

  Pictet-Spengler（PS）反应是用各种类型的底物进行的：H-Trp-OMe和二肽，N-末端Trp为芳基乙胺组分，Z保护的氨基醛和肽醛为羰基组分。我们发现，Trp衍生物的C末端部分对反应的立体选择性没有任何影响，对于Trp和二肽的简单酯，其结果相同。
• 1,3,5-Triazine Nitrogen Mustards with Different Peptide Group as Innovative Candidates for AChE and BACE1 Inhibitors
  作者：Dawid Maliszewski、Agnieszka Wróbel、Beata Kolesińska、Justyna Frączyk、Danuta Drozdowska

  DOI：10.3390/molecules26133942

  日期：——

  A series of new analogs of nitrogen mustards (4a–4h) containing the 1,3,5-triazine ring substituted with dipeptide residue were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and β-secretase (BACE1) enzymes. The AChE inhibitory activity studies were carried out using Ellman’s colorimetric method, and the BACE1 inhibitory activity studies were carried out using fluorescence

  合成了一系列含有被二肽残基取代的 1,3,5-三嗪环的氮芥 ( 4a – 4 h )的新类似物，并评估了对乙酰胆碱酯酶 (AChE) 和β-分泌酶 (BACE1) 酶的抑制作用。AChE 抑制活性研究使用 Ellman 比色法进行，BACE1 抑制活性研究使用荧光共振能量转移 (FRET) 进行。所有化合物都显示出相当大的 AChE 和 BACE1 抑制作用。对 AChE 和 BACE1 酶最有效的是化合物A和4a，AChE IC 50的抑制浓度为0.051 µM；0.055 µM 和 BACE1 IC50 = 9.00 µM；分别为 11.09 µM。
• Synthesis and conformation studies of rubiyunnanin B analogs
  作者：Na-Na Liu、Si-Meng Zhao、Jing-Feng Zhao、Guang-Zhi Zeng、Ning-Hua Tan、Jian-Ping Liu

  DOI：10.1016/j.tet.2014.06.108

  日期：2014.9

  Five new analogs 4-8 of rubiyunnanin B (1), mainly modified on the tetrapeptide subunit, were synthesized. These agents 4-8 were substituted D-Ala-L-Ala-L-Tyr(OMe)-L-Ala, D-Ala-L-Ala-L-Phe-L-Ala, D-Ala-L-Ala-L-Tyr-L-Ala, D-Ala-L-Ala-L-Pro-L-Ala, and D-Ala-L-Ala-L-Ala for the D-Ala-L-Ala-c-N-Me-Tyr(OMe)-L-Ala tetrapeptide subunit. Unlike the natural product, the synthetic agents 4-8 adopt only a single solution conformation, and the central peptide bond in the cyclodityrosine subunit of compounds 4-8 adopt trans stereochemistry. Cytotoxic activities of analogs 4-8 against three human cancer cell lines including A549, BGC-823, and HeLa were evaluated and all the five synthesized peptides exhibited no effects against the test cell lines. These compounds were also evaluated for their antiinsulin resistance and insulin sensitizing activities and none of them showed activity in these assays. (C) 2014 Elsevier Ltd. All rights reserved.
• Mithramycin 2′-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy
  作者：Yang Liu、Joseph M. Eckenrode、Yinan Zhang、Jianjun Zhang、Reiya C. Hayden、Annet Kyomuhangi、Larissa V. Ponomareva、Zheng Cui、Jürgen Rohr、Oleg V. Tsodikov、Steven G. Van Lanen、Khaled A. Shaaban、Markos Leggas、Jon S. Thorson

  DOI：10.1021/acs.jmedchem.0c01526

  日期：2020.11.25

  Mithramycin A (MTM) inhibits the oncogenic transcription factor EWS-FLI1 in Ewing sarcoma, but poor pharmacokinetics (PK) and toxicity limit its clinical use. To address this limitation, we report an efficient MTM 2'-oxime (MTM_ox) conjugation strategy for rapid MTM diversification. Comparative cytotoxicity assays of 41 MTM_ox analogues using E-twenty-six (ETS) fusion-dependent and ETS fusion-independent cancer cell lines revealed improved ETS fusion-independent/dependent selectivity indices for select 2'-conjugated analogues as compared to MTM. Luciferase-based reporter assays demonstrated target engagement at low nM concentrations, and molecular assays revealed that analogues inhibit the transcriptional activity of EWS-FLI1. These in vitro screens identified MTM_ox32E (a Phe-Trp dipeptide-based 2'-conjugate) for in vivo testing. Relative to MTM, MTM_ox32E displayed an 11-fold increase in plasma exposure and improved efficacy in an Ewing sarcoma xenograft. Importantly, these studies are the first to point to simple C3 aliphatic side-chain modification of MTM as an effective strategy to improve PK.