(3S)-3-((S)-2-acetamido-3-methylbutanamido)-4-(((2S)-1-(1-(((3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)carbamoyl)-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid | 1344157-53-4

• 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: (3S)-3-((S)-2-acetamido-3-methylbutanamido)-4-(((2S)-1-(1-(((3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)carbamoyl)-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid
• 英文别名: (3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-6-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid
• CAS: 1344157-53-4
• 化学式: C₃₁H₄₃N₅O₁₀
• 分子量: 645.71
• InChiKey: MGIHOMZITTVQKS-QYKDOZOMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  221
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoate 在 哌啶 、 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 51.83h， 生成 (3S)-3-((S)-2-acetamido-3-methylbutanamido)-4-(((2S)-1-(1-(((3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)carbamoyl)-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid
  参考文献：
  名称：

  Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors

  摘要：

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.08.020

文献信息

• Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors
  作者：Michel C. Maillard、Frederick A. Brookfield、Stephen M. Courtney、Florence M. Eustache、Mark J. Gemkow、Rebecca K. Handel、Laura C. Johnson、Peter D. Johnson、Mark A. Kerry、Florian Krieger、Mirco Meniconi、Ignacio Muñoz-Sanjuán、Jordan J. Palfrey、Hyunsun Park、Sabine Schaertl、Malcolm G. Taylor、Derek Weddell、Celia Dominguez

  DOI：10.1016/j.bmc.2011.08.020

  日期：2011.10

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.