AQ573188 | 167498-27-3

• 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: AQ573188
• 英文别名: benzyl ((S)-1-oxo-1-(((S)-1-oxopropan-2-yl)amino)-3-phenylpropan-2-yl)carbamate；1-Propanal, (2S)-2-[N-(benzyloxycarbonyl-(S)-phenylalanyl)amino]-；benzyl N-[(2S)-1-oxo-1-[[(2S)-1-oxopropan-2-yl]amino]-3-phenylpropan-2-yl]carbamate
• CAS: 167498-27-3
• 化学式: C₂₀H₂₂N₂O₄
• 分子量: 354.406
• InChiKey: IJJYXVOSNQSZOF-YJBOKZPZSA-N

物化性质

• 沸点：
  605.6±55.0 °C(Predicted)
• 密度：
  1.188±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  84.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  亚磷酸二甲酯 、 AQ573188 在 potassium fluoride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 以58%的产率得到dimethyl 2-(N-Cbz-L-phenylalanyl-L-amino)-1-hydroxypropanephosphonate
  参考文献：
  名称：

  对组织蛋白酶C和相关酶的非常有效的，非共价的有机膦酸盐抑制剂，使用2-氨基-1-羟基链烷膦酸酯二肽进行处理。

  摘要：

  组织蛋白酶在几种人类疾病中起重要作用，因此其抑制剂的设计和合成引起了人们对当前药物化学方法的极大兴趣。由于在半胱氨酸型组织蛋白酶的活性中心中存在强的巯基亲核试剂，迄今为止，大多数策略已产生了共价抑制剂。在这里，我们介绍了一系列组织蛋白酶C的非共价β-氨基-α-羟基链烷膦酸酯二肽抑制剂，在该酶的最佳低分子量抑制剂中名列前茅。通过分子建模确定的它们的结合模式表明，该分子的羟甲基片段而不是膦酸酯部分充当肽键水解的过渡态类似物。这些二肽模拟物似乎也是其他半胱氨酸蛋白酶（如木瓜蛋白酶，

  DOI：

  10.1016/j.biochi.2013.05.006
• 作为产物：
  描述：

  N-苄氧羰基-L-苯丙氨酸 N-羟基琥珀酰亚胺酯 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 13.25h， 生成 AQ573188
  参考文献：
  名称：

  Reetz, Manfred T.; Griebenow, Nils, Liebigs Annalen, 1996, # 3, p. 335 - 348

  摘要：

  DOI：

文献信息

• Evaluation of α,β-unsaturated ketone-based probes for papain-family cysteine proteases
  作者：Zhimou Yang、Marko Fonović、Steven H.L. Verhelst、Galia Blum、Matthew Bogyo

  DOI：10.1016/j.bmc.2008.02.089

  日期：2009.2

  ketone reactive group for use in ABPs targeting the papain-family of cysteine proteases. We find that this reactive group shows highly selective labeling of cysteine cathepsins in both intact cells and total cell extracts. We observed a variable degree of background labeling that depended on the type of tag and linker used in the probe synthesis. The relative ease of synthesis of this class of compounds

  基于活性的蛋白质组学领域利用小分子活性位点探针来监测酶蛋白的不同子集。虽然许多反应性官能团已应用于针对不同蛋白酶家族的基于活性的探针 (ABP)，但仍然需要进一步评估用于 ABP 的新探针支架和反应性官能团。在本研究中，我们评估了 α,β-不饱和酮反应基团在靶向半胱氨酸蛋白酶木瓜蛋白酶家族的 ABP 中的效用。我们发现该反应基团在完整细胞和总细胞提取物中均显示出对半胱氨酸组织蛋白酶的高度选择性标记。我们观察到不同程度的背景标记，这取决于探针合成中使用的标签和接头的类型。
• Peptide Fragment Coupling Using a Continuous-Flow Photochemical Rearrangement of Nitrones
  作者：Yuan Zhang、Melissa L. Blackman、Andrew B. Leduc、Timothy F. Jamison

  DOI：10.1002/anie.201300504

  日期：2013.4.8

  amide bond formation by way of a continuous‐flow photochemical rearrangement of nitrones was described (see scheme). Simple aryl‐alkyl amide bonds as well as complex peptide bonds were constructed efficiently with a residence time less than 20 minutes. A tetrapeptide was synthesized in this way and the method could be applied to peptide fragment coupling.

  顺其自然通过被描述硝酮的连续流动光化学重排的方式（参见方案）用于酰胺键形成的一般方法：。简单的芳基-烷基酰胺键以及复杂的肽键可在不到20分钟的停留时间内高效构建。用这种方法合成了四肽，该方法可用于肽片段的偶联。
• Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors
  作者：Karl A. Scheidt、William R. Roush、James H. McKerrow、Paul M. Selzer、Elizabeth Hansell、Philip J. Rosenthal

  DOI：10.1016/s0968-0896(98)80022-9

  日期：1998.12

  Conformationally constrained gamma-lactams containing electrophilic aldehyde (12, 17, 18, 25, 26, and 29) or vinyl sulfone (43, 44, and 46) units were synthesized. Constrained lactam 26 had IC50 values of ca. 20 nM against the Leishmania major protease and ca. 50 nM versus falcipain, an important cysteine protease isolated from Plasmodium falciparum. However, all of the conformationally constrained inhibitors

  半胱氨酸蛋白酶的抑制作用已被研究作为一种抗击寄生虫病（如恰加斯氏病，利什曼病和疟疾）的策略。Cruzain是锥虫锥虫的主要半胱氨酸蛋白酶，锥虫是南美锥虫病的病原体。使用氟甲基酮抑制剂1（Cbz-Phe-Ala-FMK）共价灭活的克鲁萨因的晶体结构作为模板来设计潜在的抑制剂。合成了含有亲电子醛（12、17、18、25、26和29）或乙烯基砜（43、44和46）单元的构象受限的γ-内酰胺。受约束的内酰胺26的IC50值为ca。抗利什曼原虫主要蛋白酶20 nM，与falcipain相比为50 nM，falcipain是一种从恶性疟原虫分离的重要半胱氨酸蛋白酶。然而，事实证明它是一种很好的Cruzain抑制剂，其二阶抑制速率常数（k（inact）/ Ki）为634,000s（-1）M（-1）。用在P2位上含有α-甲基苯基丙氨酸残基的无环抑制剂30和51也观察到活性的显着降低。这些数据表明，吡咯烷酮
• Synthesis of amino acid-derived imidazoles from enantiopure N-protected α-amino glyoxals
  作者：Michelle Groarke、M.Anthony McKervey、Mark Nieuwenhuyzen

  DOI：10.1016/s0040-4039(99)02267-4

  日期：2000.2

  A range of novel imidazoles, including three histidine derivatives, with chiral side chains derived from amino acids and dipeptides have been synthesised from N-Cbz-protected alpha-amino glyoxals. (C) 2000 Elsevier Science Ltd. All rights reserved.
• Development of α-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease
  作者：Youngchool Choe、Linda S. Brinen、Mark S. Price、Juan C. Engel、Meinolf Lange、Corinna Grisostomi、Scott G. Weston、Peter V. Pallai、Hong Cheng、Larry W. Hardy、David S. Hartsough、Marsha McMakin、Robert F. Tilton、Carmen M. Baldino、Charles S. Craik

  DOI：10.1016/j.bmc.2004.12.053

  日期：2005.3

  Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of alpha-ketoamide-, alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1 ' residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3 angstrom crystallographic structure of cruzain bound with one of the alpha-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization. (c) 2005 Elsevier Ltd. All rights reserved.