(S)-tert-butyl (3-(1H-indol-3-yl)-1-oxo-1-(phenethylamino)propan-2-yl)carbamate | 613675-78-8

• 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: (S)-tert-butyl (3-(1H-indol-3-yl)-1-oxo-1-(phenethylamino)propan-2-yl)carbamate
• 英文别名: tert-butyl N-[(2S)-3-(1H-indol-3-yl)-1-oxo-1-(2-phenylethylamino)propan-2-yl]carbamate
• CAS: 613675-78-8
• 化学式: C₂₄H₂₉N₃O₃
• 分子量: 407.513
• InChiKey: JOMLKWADXUZRQE-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  83.2
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl (3-(1H-indol-3-yl)-1-oxo-1-(phenethylamino)propan-2-yl)carbamate 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 0.5h， 生成
  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
• 作为产物：
  描述：

  L-色氨酸 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 4.5h， 生成 (S)-tert-butyl (3-(1H-indol-3-yl)-1-oxo-1-(phenethylamino)propan-2-yl)carbamate
  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

• Virtual Screening of Peptide and Peptidomimetic Fragments Targeted to Inhibit Bacterial Dithiol Oxidase DsbA
  作者：Wilko Duprez、Prabhakar Bachu、Martin J. Stoermer、Stephanie Tay、Róisín M. McMahon、David P. Fairlie、Jennifer L. Martin

  DOI：10.1371/journal.pone.0133805

  日期：——

  Antibacterial drugs with novel scaffolds and new mechanisms of action are desperately needed to address the growing problem of antibiotic resistance. The periplasmic oxidative folding system in Gram-negative bacteria represents a possible target for anti-virulence antibacterials. By targeting virulence rather than viability, development of resistance and side effects (through killing host native microbiota) might be minimized. Here, we undertook the design of peptidomimetic inhibitors targeting the interaction between the two key enzymes of oxidative folding, DsbA and DsbB, with the ultimate goal of preventing virulence factor assembly. Structures of DsbB - or peptides - complexed with DsbA revealed key interactions with the DsbA active site cysteine, and with a hydrophobic groove adjacent to the active site. The present work aimed to discover peptidomimetics that target the hydrophobic groove to generate non-covalent DsbA inhibitors. The previously reported structure of a Proteus mirabilis DsbA active site cysteine mutant, in a non-covalent complex with the heptapeptide PWATCDS, was used as an in silico template for virtual screening of a peptidomimetic fragment library. The highest scoring fragment compound and nine derivatives were synthesized and evaluated for DsbA binding and inhibition. These experiments discovered peptidomimetic fragments with inhibitory activity at millimolar concentrations. Although only weakly potent relative to larger covalent peptide inhibitors that interact through the active site cysteine, these fragments offer new opportunities as templates to build non-covalent inhibitors. The results suggest that non-covalent peptidomimetics may need to interact with sites beyond the hydrophobic groove in order to produce potent DsbA inhibitors.

  迫切需要具有新型骨架和新作用机制的抗菌药物来解决日益严重的抗生素抗药性问题。革兰氏阴性菌中的周质氧化折叠系统代表了抗毒力抗菌药物可能的靶点。通过针对毒力而非生存能力，可能最大限度地减少耐药性的发展和副作用（通过杀死宿主的原生微生物群）。在此，我们进行了设计，旨在针对氧化折叠的两个关键酶DsbA和DsbB之间的相互作用，设计出肽模拟物抑制剂，最终目标是阻止毒力因子组装。DsbB或肽与DsbA复合物的结构揭示了与DsbA活性位点半胱氨酸以及活性位点附近的一个疏水性凹槽的关键相互作用。目前的工作目标是发现靶向疏水性凹槽的肽模拟物，以生成非共价DsbA抑制剂。先前报道的变形杆菌DsbA活性位点半胱氨酸突变体的结构，在非共价复合物中与七肽PWATCDS结合，被用作计算机模拟筛选肽模拟物片段库的模板。得分最高的片段化合物及其九个衍生物被合成，并评估其DsbA结合和抑制作用。这些实验发现了在毫摩尔浓度下具有抑制活性的肽模拟物片段。尽管相对于通过活性位点半胱氨酸相互作用的大分子共价肽抑制剂而言，这些片段的效力较弱，但它们提供了作为构建非共价抑制剂模板的新机会。结果表明，非共价肽模拟物可能需要与疏水性凹槽以外的位点相互作用，才能产生强效的DsbA抑制剂。
• C ring may be dispensable for β-carboline: Design, synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of β-carboline alkaloids
  作者：Yuanqiong Huang、Yongxian Liu、Yuxiu Liu、Hongjian Song、Qingmin Wang

  DOI：10.1016/j.bmc.2015.08.016

  日期：2016.2

  According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure–activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against

  根据我们先前对β-咔啉生物合成的研究和最新研究，并采用逆向思维策略，合成了色氨酸，β-咔啉生物碱的生物合成前体及其衍生物，以及它们的生物活性和构效关系被研究了。这项生物测定结果表明，这些化合物对烟草花叶病毒（TMV）表现出良好的抑制活性。尤其是（S）-2-氨基-3-（1 H-吲哚-3-基）-N-辛基丙酰胺（4）（63.3±2.1％，67.1±1.9％，68.7±1.3％和64.5±3.1％， 500μg/ mL）在体外和体内均表现出最佳的抗病毒活性。化合物4选择该化合物用于野外试验和急性口服毒性试验，结果表明该化合物在野外具有良好的抗TMV活性，而急性口服毒性较低。我们还发现这些化合物显示出抗真菌活性和杀虫活性。
• Small-Molecule Inhibitors That Target Protein-Protein Interactions in the RAD51 Family of Recombinases
  作者：Duncan E. Scott、Anthony G. Coyne、Ashok Venkitaraman、Tom L. Blundell、Chris Abell、Marko Hyvönen

  DOI：10.1002/cmdc.201402428

  日期：2015.2

  The development of small molecules that inhibit protein–protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the development of indole‐based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51. RAD51 is an ATP‐dependent recombinase that plays a key role in the repair of double‐strand DNA breaks. It both self‐associates

  抑制蛋白质与蛋白质相互作用的小分子的发展仍然是化学生物学和药物发现中的挑战。在这里，我们报道了结合吲哚基片段的发展，该片段结合在RAD51人性化替代物的浅表囊中。RAD51是一种依赖于ATP的重组酶，在双链DNA断裂的修复中起关键作用。它既可以自缔合，与DNA形成细丝结构，又可以通过常见的“ FxxA”四肽基序与BRCA2蛋白相互作用。我们精心设计了先前确定的靶向FxxA序列位点的片段，并开发了比初始片段强约500倍的小分子抑制剂。铅化合物与BRCA2衍生的Ac-FHTA-NH 2竞争肽和RAD51的自缔合肽，但它们对ATP结合没有影响。这项研究是首次报道针对这一具有挑战性的目标的小分子量片段的研究。
• Condensation of α-Amino Acid with Amine in the Absence of a Coupling Agent
  作者：Jun-ichi Yamaguchi、Shinya Nagai、Emi Fukuoka、Takayuki Suyama

  DOI：10.1246/cl.2003.830

  日期：2003.9

  Treatment of N-(4-nitrophenoxycarbonyl)amino acid with an equimolar amount of amine in the absence of a coupling agent gave the corresponding α-amino acid amide in high yield.

  在没有偶联剂的情况下，用等摩尔量的胺处理 N-(4-硝基苯氧羰基)氨基酸，可以高产率地得到相应的 α-氨基酸酰胺。
• Development of Peptide 3D Structure Mimetics:  Rational Design of Novel Peptoid Cholecystokinin Receptor Antagonists
  作者：Caroline M. R. Low、James W. Black、Howard B. Broughton、Ildiko M. Buck、Jonathan M. R. Davies、David J. Dunstone、Robert A. D. Hull、S. Barret Kalindjian、Iain M. McDonald、Michael J. Pether、Nigel P. Shankley、Katherine I. M. Steel

  DOI：10.1021/jm000937a

  日期：2000.9.1

  The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly(29)-Trp(30)-Met(31)-Asp(32)-Phe(33)-NH2. Nevertheless, this congruence has not precluded using this structure to develop selective ligands for either CCK1 or CCK2 receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK1 tripeptide antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pK(B) 6.8 +/- 0.3). Molecular modeling was used to identify the bioactive conformation of these CCK1-selective compounds and prompted the design of new peptoid structures. We aimed to maintain the conformation of the parent series by exploiting patterns of hydrogen-bonding and pi-stacking interactions present in the original molecule, rather than introducing additional covalent bonds. The prototype, N-(succinyl-o-Asp-2-phenylethylamido)-L-Trp-2-( 2-naphthyl) ethylamide, was a potent and selective CCK1 antagonist (pK(B) 7.2 +/- 0.3). Furthermore, the new series showed patterns of biological activity that mirrored those of the parent tripeptides. These compounds contain elements of both peptide primary and secondary structure and represent a novel approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK1 antagonist with a conformation of CCK30-33 that others have proposed to be responsible for its activity at the CCK2 receptor. The results suggest that CCK1 and CCK2 receptors recognize enatiomeric dispositions of the Trp(30) indole, Asp(32) carboxylic acid, and C-terminal phenyl groups arrayed about a common backbone configuration. This "functional chirality" may underpin the mechanism by which these closely related receptor systems bind CCK30-33 and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands.