N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl-O-(ethenylsulfonyl)-N-4-pentyn-1-yl-L-tyrosinamide

• 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: N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl-O-(ethenylsulfonyl)-N-4-pentyn-1-yl-L-tyrosinamide
• 英文别名: [4-[(2S)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]-3-oxo-3-(pent-4-ynylamino)propyl]phenyl] ethenesulfonate
• 化学式: C₃₀H₃₇N₃O₇S
• 分子量: 583.706
• InChiKey: RNMDSOKRNOMQFX-UIOOFZCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  41
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  148
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-氯乙烷磺酰氯 、 在 三乙胺 作用下， 以72%的产率得到N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanyl-O-(ethenylsulfonyl)-N-4-pentyn-1-yl-L-tyrosinamide
  参考文献：
  名称：

  Small Molecule Probe Suitable for In Situ Profiling and Inhibition of Protein Disulfide Isomerase

  摘要：

  Proper folding of cellular proteins is assisted by protein disulfide isomerases (PDIs) in the endoplasmic reticulum of mammalian cells. Of the at least 21 PDI family members known in humans, the 57-kDa PDI has been found to be a potential therapeutic target for a variety of human diseases including cancer and neurodegenerative diseases. Consequently, small molecule PDI-targeting inhibitors have been actively pursued in recent years, and thus far, compounds possessing moderate inhibitory activities (IC50 between 0.1 and 100 mu M against recombinant PDI) have been discovered. In this article, by using in situ proteome profiling experiments in combination with in vitro PDI enzymatic inhibition assays, we have discovered a phenyl vinyl sulfonate-containing small molecule (P1; shown) as a relatively potent and specific inhibitor of endogenous human PDI in several mammalian cancer cells (e.g., GI(50) similar to 4 mu M). It also possesses an IC50 value of 1.7 +/- 0.4 mu M in an in vitro insulin aggregation assay. Our results indicate P1 is indeed a novel, cell-permeable small molecule PDI inhibitor, and the electrophilic vinyl sulfonate scaffold might serve as a starting point for future development of next-generation PDI inhibitors and probes.

  DOI：

  10.1021/cb4002602

文献信息

• Small Molecule Probe Suitable for <i>In Situ</i> Profiling and Inhibition of Protein Disulfide Isomerase
  作者：Jingyan Ge、Chong-Jing Zhang、Lin Li、Li Min Chong、Xiaoyuan Wu、Piliang Hao、Siu Kwan Sze、Shao Q. Yao

  DOI：10.1021/cb4002602

  日期：2013.11.15

  Proper folding of cellular proteins is assisted by protein disulfide isomerases (PDIs) in the endoplasmic reticulum of mammalian cells. Of the at least 21 PDI family members known in humans, the 57-kDa PDI has been found to be a potential therapeutic target for a variety of human diseases including cancer and neurodegenerative diseases. Consequently, small molecule PDI-targeting inhibitors have been actively pursued in recent years, and thus far, compounds possessing moderate inhibitory activities (IC50 between 0.1 and 100 mu M against recombinant PDI) have been discovered. In this article, by using in situ proteome profiling experiments in combination with in vitro PDI enzymatic inhibition assays, we have discovered a phenyl vinyl sulfonate-containing small molecule (P1; shown) as a relatively potent and specific inhibitor of endogenous human PDI in several mammalian cancer cells (e.g., GI(50) similar to 4 mu M). It also possesses an IC50 value of 1.7 +/- 0.4 mu M in an in vitro insulin aggregation assay. Our results indicate P1 is indeed a novel, cell-permeable small molecule PDI inhibitor, and the electrophilic vinyl sulfonate scaffold might serve as a starting point for future development of next-generation PDI inhibitors and probes.