N-benzyltryptophanamide hydrochloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-benzyltryptophanamide hydrochloride
• 英文别名: (2S)-2-amino-N-benzyl-3-(1H-indol-3-yl)propanamide hydrochloride；(2S)-2-amino-N-benzyl-3-(1H-indol-3-yl)propanamide;hydrochloride
• 化学式: C₁₈H₁₉N₃O*ClH
• 分子量: 329.829
• InChiKey: JEHRQXDQMYCCJX-NTISSMGPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.36
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  72.5
• 氢给体数：
  3
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-benzyltryptophanamide hydrochloride 在 氢氧化钾 、 盐酸羟胺 、 三乙胺 、 N,N'-羰基二咪唑 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 (2R)-N-[(2S)-1-(benzylamino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-N'-hydroxy-2-(2-methylpropyl)butanediamide
  参考文献：
  名称：

  Matrix Metalloproteinase Inhibitors:  A Structure−Activity Study

  摘要：

  Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.

  DOI：

  10.1021/jm970494j
• 作为产物：
  描述：

  N-叔丁氧羰基-L-色氨酸 在 盐酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 4.5h， 生成 N-benzyltryptophanamide hydrochloride
  参考文献：
  名称：

  具有吲哚帽作为新型组蛋白脱乙酰基酶抑制剂的N1-羟基对苯二甲酰胺衍生物的设计，合成和初步生物活性评估。

  摘要：

  组蛋白脱乙酰基酶抑制剂（HDACIs）已被广泛认为是治疗癌症的重要方法。在我们努力开发新型组蛋白脱乙酰基酶抑制剂（HDACIs）作为潜在的抗癌药的过程中，设计并合成了一系列带有吲哚帽基团的N1-羟基对苯二甲酰胺衍生物。化合物12m被确定为最有效的化合物（针对Hela核提取物的IC50 =0.074μM），并显示出比阳性对照SAHA（IC50 =0.131μM）更高的抑制活性，这也通过进一步的分子对接研究验证了该化合物的活性位点。 HDAC2。抑制HDAC的选择性结果显示12m具有与PXD101相当的总体同工型选择性分布。另外，根据初步肿瘤细胞筛选的结果，具有代表性的化合物在下一个抗增殖活性试验中显示出比SAHA更有效或可比的功效。总的来说，结果鼓励该化学模板的进一步开发以提供更有效的类似物如HDACI。本文受版权保护。版权所有。

  DOI：

  10.1111/cbdd.12819

文献信息

• 2-Amido-3-(1H-Indol-3-yl)-N-Substitued-Propanamides as a New Class of Falcipain-2 Inhibitors. 1. Design, Synthesis, Biological Evaluation and Binding Model Studies
  作者：Jin Zhu、Tong Chen、Lili Chen、Weiqiang Lu、Peng Che、Jin Huang、Honglin Li、Jian Li、Hualiang Jiang

  DOI：10.3390/molecules14010494

  日期：——

  The Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is an important cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites. The discovery of new FP-2 inhibitors is now a hot topic in the search for potential malaria treatments. In this study, a series of novel small molecule FP-2 inhibitors have been designed and synthesized based on three regional optimizations of the lead (R)-2-phenoxycarboxamido-3-(1H-indol-3-yl)-N-benzylpropanamide(1), which was identified using structure-based virtual screening in conjunction with surface plasmon resonance (SPR)-based binding assays. Four compounds – 1, 2b, 2k and 2l –showed moderate FP-2 inhibition activity, with IC50 values of 10.0-39.4 μM, and the inhibitory activityof compound 2k was ~3-fold better than that of the prototype compound 1 and may prove useful for the development of micromolar level FP-2 inhibitors. Preliminary SAR data was obtained, while molecular modeling revealed that introduction of H-bond donor or/and acceptor atoms to the phenyl ring moiety in the C region would be likely to produce some additional H-bond interactions, which should consequently enhance molecular bioactivity.

  恶性疟原虫半胱氨酸蛋白酶恶性疟原虫滋养体-2（FP-2）是一种重要的半胱氨酸蛋白酶，也是红细胞恶性疟原虫滋养体的重要血红蛋白酶。发现新的 FP-2 抑制剂是目前寻找潜在疟疾治疗方法的热门话题。在本研究中，基于对先导物 (R)-2-phenoxycarboxamido-3-(1H-indol-3-yl)-N-benzylpropanamide(1) 的三次区域优化，设计并合成了一系列新型小分子 FP-2 抑制剂。1、2b、2k 和 2l 四种化合物显示出中等程度的 FP-2 抑制活性，IC50 值为 10.0-39.4 μM，其中化合物 2k 的抑制活性比原型化合物 1 的抑制活性高出约 3 倍，可能有助于开发微摩尔水平的 FP-2 抑制剂。研究获得了初步的 SAR 数据，而分子模型显示，在 C 区的苯环分子中引入 H 键供体或/和受体原子可能会产生一些额外的 H 键相互作用，从而提高分子的生物活性。
• Novel potent substance P and neurokinin A receptor antagonists. Conception, synthesis and biological evaluation of indolizine derivatives
  作者：Régis Millet、Juozas Domarkas、Benoı̂t Rigo、Laurence Goossens、Jean-François Goossens、Raymond Houssin、Jean-Pierre Hénichart

  DOI：10.1016/s0968-0896(02)00144-x

  日期：2002.9

  Exploration of SAR around dual NK1/NK2 antagonist Cbz-Gly-Leu-Trp-OBzl(CF3)(2) and its derivatives disclosed the essential requirements for more potent dual NK1/NK2 binding, We report here the synthesis and the biological properties of a novel series of indolizine including, pharmacophoric elements. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Structure optimization and preliminary bioactivity evaluation of N-hydroxybenzamide-based HDAC inhibitors with Y-shaped cap
  作者：Chenggong Yu、Feng He、Ying Qu、Qiuqiong Zhang、Jiahui Lv、Xiangna Zhang、Ana Xu、Pannan Miao、Jingde Wu

  DOI：10.1016/j.bmc.2018.02.033

  日期：2018.5

  Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA. (C) 2018 Elsevier Ltd. All rights reserved.
• Matrix Metalloproteinase Inhibitors:  A Structure−Activity Study
  作者：Daniel E. Levy、France Lapierre、Weisheng Liang、Wenqing Ye、Christopher W. Lange、Xiaoyuan Li、Damian Grobelny、Marie Casabonne、David Tyrrell、Kevin Holme、Alex Nadzan、Richard E. Galardy

  DOI：10.1021/jm970494j

  日期：1998.1.1

  Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.
• Design, synthesis, and preliminary bioactivity evaluation of <i>N</i> ¹ -hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors
  作者：Xue Wang、Xiaoyang Li、Jingyao Li、Jinning Hou、Ying Qu、Chenggong Yu、Feng He、Wenfang Xu、Jingde Wu

  DOI：10.1111/cbdd.12819

  日期：2017.1

  Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1 -hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50 =0.074muM against

  组蛋白脱乙酰基酶抑制剂（HDACIs）已被广泛认为是治疗癌症的重要方法。在我们努力开发新型组蛋白脱乙酰基酶抑制剂（HDACIs）作为潜在的抗癌药的过程中，设计并合成了一系列带有吲哚帽基团的N1-羟基对苯二甲酰胺衍生物。化合物12m被确定为最有效的化合物（针对Hela核提取物的IC50 =0.074μM），并显示出比阳性对照SAHA（IC50 =0.131μM）更高的抑制活性，这也通过进一步的分子对接研究验证了该化合物的活性位点。 HDAC2。抑制HDAC的选择性结果显示12m具有与PXD101相当的总体同工型选择性分布。另外，根据初步肿瘤细胞筛选的结果，具有代表性的化合物在下一个抗增殖活性试验中显示出比SAHA更有效或可比的功效。总的来说，结果鼓励该化学模板的进一步开发以提供更有效的类似物如HDACI。本文受版权保护。版权所有。