(2S)-N-[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]-N'-(2,2-dimethylpropyl)-2-(3-phenylpropanoylamino)butanediamide | 1252801-28-7

• 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: (2S)-N-[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]-N'-(2,2-dimethylpropyl)-2-(3-phenylpropanoylamino)butanediamide
• CAS: 1252801-28-7
• 化学式: C₃₃H₄₀ClN₅O₄
• 分子量: 606.165
• InChiKey: KPRRNVVHNZTZFT-NSOVKSMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  43
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  129
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  邻氯苯甲胺 在 N-甲基吗啉 、 盐酸 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.0h， 生成 (2S)-N-[(2S)-1-[(2-chlorophenyl)methylamino]-1-oxo-3-pyridin-3-ylpropan-2-yl]-N'-(2,2-dimethylpropyl)-2-(3-phenylpropanoylamino)butanediamide
  参考文献：
  名称：

  Optimization of a series of dipeptides with a P3 β-neopentyl asparagine residue as non-covalent inhibitors of the chymotrypsin-like activity of human 20S proteasome

  摘要：

  通过共价抑制剂抑制蛋白酶体是一种临床验证过的抗癌疗法。我们在此报告，含有P3新戊酰胺残基的二肽能够有效地、可逆地、非共价地选择性抑制20S蛋白酶体在体外和细胞内的胰蛋白酶活性。化合物20与酵母20S的X射线结构揭示了新戊基团在20S β5亚基S3结合口袋中的疏水键结合作用的重要性。在多项检测中，四种化合物的效力与硼酸抑制剂相当。

  DOI：

  10.1039/c2md20060k

文献信息

• Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S β5-subunit
  作者：Christopher Blackburn、Kenneth M. Gigstad、Paul Hales、Khristofer Garcia、Matthew Jones、Frank J. Bruzzese、Cynthia Barrett、Jane X. Liu、Teresa A. Soucy、Darshan S. Sappal、Nancy Bump、Edward J. Olhava、Paul Fleming、Lawrence R. Dick、Christopher Tsu、Michael D. Sintchak、Jonathan L. Blank

  DOI：10.1042/bj20100383

  日期：2010.9.15

  The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of a novel series of non-covalent di-peptide inhibitors of the proteasome used on a capped tri-peptide that was first identified by high-throughput screening of a library of approx. 350000 compounds for inhibitors of the ubiquitin–proteasome system in cells. We show that these compounds are entirely selective for the β5 (chymotrypsin-like) site over the β1 (caspase-like) and β2 (trypsin-like) sites of the 20S core particle of the proteasome, and over a panel of less closely related proteases. Compound optimization, guided by X-ray crystallography of the liganded 20S core particle, confirmed their non-covalent binding mode and provided a structural basis for their enhanced in vitro and cellular potencies. We demonstrate that such compounds show low nanomolar IC50 values for the human 20S β5 site in vitro, and that pharmacological inhibition of this site in cells is sufficient to potently inhibit the degradation of a tetra-ubiquitin–luciferase reporter, activation of NFκB (nuclear factor κB) in response to TNF-α (tumour necrosis factor-α) and the proliferation of cancer cells. Finally, we identified capped di-peptides that show differential selectivity for the β5 site of the constitutively expressed proteasome and immunoproteasome in vitro and in B-cell lymphomas. Collectively, these studies describe the synthesis, activity and binding mode of a new series of non-covalent proteasome inhibitors with unprecedented potency and selectivity for the β5 site, and which can discriminate between the constitutive proteasome and immunoproteasome in vitro and in cells.

  哺乳动物 26S 蛋白酶体是一种 2500 kDa 的多催化复合体，参与细胞内蛋白质的降解。我们描述了一系列新型蛋白酶体非共价二肽抑制剂的合成和特性，这些抑制剂使用了一种带帽三肽，是通过高通量筛选细胞中泛素-蛋白酶体系统抑制剂的约 35 万个化合物库首次发现的。我们的研究表明，这些化合物对蛋白酶体 20S 核心颗粒的 β5（类糜蛋白酶）位点具有完全的选择性，而对 β1（类 Caspase）和 β2（类胰蛋白酶）位点则没有选择性。以配体 20S 核心颗粒的 X 射线晶体学为指导，对化合物进行了优化，确认了它们的非共价结合模式，并为它们增强体外和细胞效力提供了结构基础。我们证明，这些化合物在体外对人类 20S β5 位点的 IC50 值很低，而且在细胞中对该位点的药理抑制足以有效抑制四泛素-荧光素酶报告物的降解、NFκB（核因子κB）对 TNF-α（肿瘤坏死因子-α）的活化以及癌细胞的增殖。最后，我们发现了在体外和 B 细胞淋巴瘤中对组成型表达蛋白酶体和免疫蛋白酶体的 β5 位点具有不同选择性的封端二肽。总之，这些研究描述了一系列新的非共价蛋白酶体抑制剂的合成、活性和结合模式，它们具有前所未有的效力和对β5位点的选择性，并能在体外和细胞内区分组成型蛋白酶体和免疫蛋白酶体。
• Optimization of a series of dipeptides with a P3 β-neopentyl asparagine residue as non-covalent inhibitors of the chymotrypsin-like activity of human 20S proteasome
  作者：Christopher Blackburn、Cynthia Barrett、Jonathan L. Blank、Frank J. Bruzzese、Nancy Bump、Lawrence R. Dick、Paul Fleming、Khristofer Garcia、Paul Hales、Matthew Jones、Jane X. Liu、Masayuki Nagayoshi、Darshan S. Sappal、Michael D. Sintchak、Christopher Tsu、Cindy Xia、Xiansi Zhou、Kenneth M. Gigstad

  DOI：10.1039/c2md20060k

  日期：——

  Inhibition of the proteasome by covalent inhibitors is a clinically proven anti-cancer therapy. We report here that dipeptides with a P3 neopentyl Asn residue are potent, reversible, non-covalent inhibitors selective for the chymotryptic activity of the 20S proteasome in vitro and in cells. The X-ray structure of compound 20 in complex with yeast 20S reveals the importance of hydrophobic bonding interactions of the neopentyl group within the S3 binding pocket of the 20S β5 sub-unit. Four compounds show comparable potencies to boronic acid inhibitors in a panel of assays.

  通过共价抑制剂抑制蛋白酶体是一种临床验证过的抗癌疗法。我们在此报告，含有P3新戊酰胺残基的二肽能够有效地、可逆地、非共价地选择性抑制20S蛋白酶体在体外和细胞内的胰蛋白酶活性。化合物20与酵母20S的X射线结构揭示了新戊基团在20S β5亚基S3结合口袋中的疏水键结合作用的重要性。在多项检测中，四种化合物的效力与硼酸抑制剂相当。