(2S)-2-[[(2S)-3-[4-(aminomethyl)phenyl]-2-[[(2S)-2-azido-3-phenylpropanoyl]amino]propanoyl]amino]-N-[(E,2S)-1-(4-aminophenyl)-4-methylsulfonylbut-3-en-2-yl]-4-methylpentanamide | 1421639-74-8

• 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)-2-[[(2S)-3-[4-(aminomethyl)phenyl]-2-[[(2S)-2-azido-3-phenylpropanoyl]amino]propanoyl]amino]-N-[(E,2S)-1-(4-aminophenyl)-4-methylsulfonylbut-3-en-2-yl]-4-methylpentanamide
• CAS: 1421639-74-8
• 化学式: C₃₆H₄₆N₈O₅S
• 分子量: 702.878
• InChiKey: KVWGALLOHHTTDN-BQYZZHICSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  50
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  196
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  Fmoc-4-氨基-L-苯丙氨酸 在 lithium aluminium tetrahydride 、 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 水 、 sodium hydride 、 碳酸氢钠 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 32.67h， 生成 (2S)-2-[[(2S)-3-[4-(aminomethyl)phenyl]-2-[[(2S)-2-azido-3-phenylpropanoyl]amino]propanoyl]amino]-N-[(E,2S)-1-(4-aminophenyl)-4-methylsulfonylbut-3-en-2-yl]-4-methylpentanamide
  参考文献：
  名称：

  Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites

  摘要：

  Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that cornbinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antincoplastic activity than combinations currently used clinically.

  DOI：

  10.1021/jm3016987

文献信息

• Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites
  作者：Paul P. Geurink、Wouter A. van der Linden、Anne C. Mirabella、Nerea Gallastegui、Gerjan de Bruin、Annet E. M. Blom、Mathias J. Voges、Elliot D. Mock、Bogdan I. Florea、Gijs A. van der Marel、Christoph Driessen、Mario van der Stelt、Michael Groll、Herman S. Overkleeft、Alexei F. Kisselev

  DOI：10.1021/jm3016987

  日期：2013.2.14

  Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that cornbinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antincoplastic activity than combinations currently used clinically.