(2S)-2-[4-[(1S,2S)-1-amino-2-methylbutyl]triazol-1-yl]-1-[4-[4-[4-[(2S)-2-[4-[(1S,2S)-1-amino-2-methylbutyl]triazol-1-yl]-3-(4-hydroxyphenyl)propanoyl]piperazin-1-yl]-6-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethylamino]-1,3,5-triazin-2-yl]piperazin-1-yl]-3-(4-hydroxyphenyl)propan-1-one | 1192378-55-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (2S)-2-[4-[(1S,2S)-1-amino-2-methylbutyl]triazol-1-yl]-1-[4-[4-[4-[(2S)-2-[4-[(1S,2S)-1-amino-2-methylbutyl]triazol-1-yl]-3-(4-hydroxyphenyl)propanoyl]piperazin-1-yl]-6-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethylamino]-1,3,5-triazin-2-yl]piperazin-1-yl]-3-(4-hydroxyphenyl)propan-1-one
• CAS: 1192378-55-4
• 化学式: C₅₂H₇₄N₁₆O₇
• 分子量: 1035.26
• InChiKey: ZAYRSYRBEBTRDO-ZGLAXZLGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  75
• 可旋转键数：
  27
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  279
• 氢给体数：
  5
• 氢受体数：
  19

反应信息

• 作为反应物：
  描述：

  、 (2S)-2-[4-[(1S,2S)-1-amino-2-methylbutyl]triazol-1-yl]-1-[4-[4-[4-[(2S)-2-[4-[(1S,2S)-1-amino-2-methylbutyl]triazol-1-yl]-3-(4-hydroxyphenyl)propanoyl]piperazin-1-yl]-6-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethylamino]-1,3,5-triazin-2-yl]piperazin-1-yl]-3-(4-hydroxyphenyl)propan-1-one 在 copper(II) sulfate 、 sodium ascorbate 、 三[(1-苄基-1H-1,2,3-三唑-4-基)甲基]胺 作用下， 以 水 、 二甲基亚砜 为溶剂， 反应 24.0h， 生成
  参考文献：
  名称：

  Small Molecule Ligands for Active Targeting of TrkC-Expressing Tumor Cells

  摘要：

  A small molecule motif was used in "active targeting" to deliver cytotoxic substances into tumor cells that express the TrkC receptor. Underlying this study was the hypothesis that internalization of targeted conjugates into cells would be facile if mediated by receptor binding and receptor ligand internalization. Initial experiments using 6-mercaptopurine gave encouraging data but demonstrated the importance of maintaining solubility and high cytotoxicity. Conjugates of the targeting agent with a cytotoxic rosamine (similar to a rhodamine) were more successful. Targeting of TrkC was observed, validated in a series of competition experiments featuring other TrkC ligands, and accumulation into lysosomes was observed, as expected for receptor-mediated internalization.

  DOI：

  10.1021/ml300227d

文献信息

• TrkC-Targeted Kinase Inhibitors And PROTACs
  作者：Bosheng Zhao、Kevin Burgess

  DOI：10.1021/acs.molpharmaceut.9b00673

  日期：2019.10.7

  A small molecule motif (IY-IY), which binds the tropomyosin receptor kinase C (TrkC), was used to deliver the promiscuous kinase inhibitor (KI) dasatinib into breast cancer. Conjugates with noncleavable (1) and cleavable (2) linkers were compared in cellular assays and shown to have more impact on the cell viabilities of TrkC+ breast cancer cells over TrkC- epithelial cells. The IY-IY fragment was

  与原肌球蛋白受体激酶C（TrkC）结合的小分子基序（IY-IY）用于将混杂激酶抑制剂（KI）达沙替尼递送至乳腺癌中。在细胞测定法中比较了具有不可切割的（1）和可切割的（2）接头的缀合物，并显示它们比TrkC-上皮细胞对TrkC +乳腺癌细胞的细胞活力有更大的影响。IY-IY片段还用于募集E3连接酶大脑，从而为转移性乳腺癌细胞中的TrkC降解提供了有效的靶向嵌合蛋白（PROTAC）。
• Double-Targeting Using a TrkC Ligand Conjugated to Dipyrrometheneboron Difluoride (BODIPY) Based Photodynamic Therapy (PDT) Agent
  作者：Anyanee Kamkaew、Kevin Burgess

  DOI：10.1021/jm4012142

  日期：2013.10.10

  A molecule 1 (IY-IY-PDT) was designed to contain a fragment (if-if) that targets the TrkC receptor and a photosensitizer that acts as an agent for photodynamic therapy (PDT). Molecule 1 had submicromolar photocytotoxicities to cells that were engineered to stably express TrkC (NIH3T3-TrkC) or that naturally express high levels of TrkC (SYSY neuroblastoma lines). Control experiments showed that 1 is not cytotoxic in the dark and has significantly less photocytotoxicity toward cells that do not express TrkC (NIH3T3-WT). Other controls featuring a similar agent 2 (YI-YI-PDT), which is identical and isomeric with 1 except that the targeting region is scrambled (a YI-YI motif, see text), showed that 1 is considerably more photocytotoxic than 2 on TrkC(+) cells. Imaging live TrkC(+) cells after treatment with a fluorescent agent 1 (IY-IY-PDT) proved that 1 permeates into TrkC(+) cells and is localized in the lysosomes. This observation indirectly indicates that agent 1 enters the cells via the TrkC receptor. Consistent with this, the dose-dependent PDT effects of 1 can be competitively reduced by the natural TrkC ligand, neurotrophin NT3.