2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethoxy)ethoxy)ethyl)thioureido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanediyl)diacetic acid | 1559003-54-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 生物素及其衍生物
• 英文名称: 2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethoxy)ethoxy)ethyl)thioureido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanediyl)diacetic acid
• CAS: 1559003-54-1
• 化学式: C₃₈H₅₈N₈O₁₄S₂
• 分子量: 915.056
• InChiKey: ZIQRHYHBVFITCS-FBLSVYJXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.91
• 重原子数：
  62.0
• 可旋转键数：
  33.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  308.97
• 氢给体数：
  10.0
• 氢受体数：
  14.0

反应信息

• 作为产物：
  描述：

  N-生物素-3,6-二氧杂辛烷-1,8-二胺 、 2-({2-[bis(carboxymethyl)amino]-3-(4-isothiocyanatophenyl)propyl}({2-[bis(carboxy methyl)amino]ethyl})amino)acetic acid 在 sodium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethoxy)ethoxy)ethyl)thioureido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanediyl)diacetic acid
  参考文献：
  名称：

  Intracellular Routing in Breast Cancer Cells of Streptavidin-Conjugated Trastuzumab Fab Fragments Linked to Biotinylated Doxorubicin-Functionalized Metal Chelating Polymers

  摘要：

  We describe the synthesis of a heterotelechelic metal-chelating polymer (Bi-MCP-Dox), a polyacrylamide with a number average degree of polymerization DPn = 50 (PDI = 1.2), with biotin (Bi) and doxorubicin (Dox) as functional chain ends and diethylenetriaminepentaacetic acid (DTPA) pendant groups as the binding sites for metal ions. We compared its behavior in cell-uptake experiments with a similar polymer (Bi-MCP) without Dox. These MCPs were complexed with trastuzumab Fab (tmFab) fragments covalently linked to streptavidin (SAv) to form tmFab-SAv-Bi-MCP-Dox and tmFab-SAv-Bi-MCP via the strong affinity between Bi and SAv. tmFab targets human epidermal growth factor receptor-2 (HER2), which is overexpressed on certain human breast cancer cells. Surface plasmon resonance (SPR) experiments with the extracellular domain (ECD) of HER2 showed that incorporation of the MCPs in these complexes had no significant effect on the association or dissociation rate with the HER2 ECD and the dissociation constants. The tmFab-complexed MCPs were subsequently labeled with In-111 (an Auger electron emitting radionuclide). Auger electrons can cause lethal DNA double strand breaks (DSBs) but only if they are emitted intracellularly and especially, in close proximity to the nucleus. To evaluate the cellular and nuclear uptake of tmFab-SAv-Bi-MCP-Dox, we incubated HER2+ SK-BR-3 human breast cancer cells with the complexes saturated with stable In3+ and visualized their distribution by confocal fluorescence microscopy, monitoring the fluorescence of Dox. In parallel, we carried out cell fractionation studies on tmFab-SAv-Bi-MCP-Dox and on tmFab-SAv-Bi-MCP labeled with In-111. Both radiolabeled complexes showed cell internalization and nuclear localization. We conclude that metal-chelating polymers with this composition appear to encourage internalization, nuclear uptake, and chromatin (DNA) binding of trastuzumab fragments modified with streptavidin in human breast cancer cells expressing HER2. Further study is needed to understand the impact of polymer charge on cellular uptake and distribution to intracellular compartments.

  DOI：

  10.1021/bm401483a