benzyl (1S)-1-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate | 1432065-36-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: benzyl (1S)-1-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 1432065-36-5
• 化学式: C₁₈H₁₉NO₃
• 分子量: 297.354
• InChiKey: YCMOFLLBVLGUQW-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  benzyl (1S)-1-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate 在 偶氮二甲酸二异丙酯 、 palladium on activated charcoal 、 氢气 、 三苯基膦 作用下， 生成 (1S)-(-)-1-phthalimidomethyl-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction

  摘要：

  A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100x more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure activity relationships support its use as a lead for our ongoing optimization (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.013
• 作为产物：
  描述：

  (S)-1,2,3,4-四氢-1-异喹啉羧酸 、 氯甲酸苄酯 在 diborane(6) 作用下， 生成 benzyl (1S)-1-(hydroxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate
  参考文献：
  名称：

  Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction

  摘要：

  A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100x more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure activity relationships support its use as a lead for our ongoing optimization (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.013

文献信息

• Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction
  作者：Longqin Hu、Sadagopan Magesh、Lin Chen、Lili Wang、Timothy A. Lewis、Yu Chen、Carol Khodier、Daigo Inoyama、Lesa J. Beamer、Thomas J. Emge、Jian Shen、John E. Kerrigan、Ah-Ng Tony Kong、Sivaraman Dandapani、Michelle Palmer、Stuart L. Schreiber、Benito Munoz

  DOI：10.1016/j.bmcl.2013.03.013

  日期：2013.5

  A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1-Nrf2 protein protein interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100x more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure activity relationships support its use as a lead for our ongoing optimization (C) 2013 Elsevier Ltd. All rights reserved.