2-((benzyloxy)carbonyl)-2-methylpropane-1,3-diyl bis(2,2,9,17-tetramethyl-4,14-dioxo-17-(8,15,15-trimethyl-3,13-dioxo-2,14-dioxa-4,8,12-triazahexadecyl)-3,15-dioxa-5,9,13-triazaoctadecan-18-oate) | 1351959-63-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-((benzyloxy)carbonyl)-2-methylpropane-1,3-diyl bis(2,2,9,17-tetramethyl-4,14-dioxo-17-(8,15,15-trimethyl-3,13-dioxo-2,14-dioxa-4,8,12-triazahexadecyl)-3,15-dioxa-5,9,13-triazaoctadecan-18-oate)
• CAS: 1351959-63-1
• 化学式: C₇₄H₁₃₂N₁₂O₂₂
• 分子量: 1541.93
• InChiKey: VKZZOCUZSYKKDI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.69
• 重原子数：
  108.0
• 可旋转键数：
  49.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  398.5
• 氢给体数：
  8.0
• 氢受体数：
  26.0

反应信息

• 作为反应物：
  描述：

  2-((benzyloxy)carbonyl)-2-methylpropane-1,3-diyl bis(2,2,9,17-tetramethyl-4,14-dioxo-17-(8,15,15-trimethyl-3,13-dioxo-2,14-dioxa-4,8,12-triazahexadecyl)-3,15-dioxa-5,9,13-triazaoctadecan-18-oate) 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以91%的产率得到
  参考文献：
  名称：

  Degradable Self-Assembling Dendrons for Gene Delivery: Experimental and Theoretical Insights into the Barriers to Cellular Uptake

  摘要：

  This paper uses a combined experimental and theoretical approach to gain unique insight into gene delivery. We report the synthesis and investigation of a new family of second-generation dendrons with four triamine surface ligands capable of binding to DNA, degradable aliphatic-ester dendritic scaffolds, and hydrophobic units at their focal points. Dendron self-assembly significantly enhances DNA binding as monitored by a range of experimental methods and confirmed by multiscale modeling. Cellular uptake studies indicate that some of these dendrons are highly effective at transporting DNA into cells (ca. 10 times better than poly(ethyleneimine), PEI). However, levels of transgene expression are relatively low (ca. 10% of PEI). This indicates that these dendrons cannot navigate all of the intracellular barriers to gene delivery. The addition of chloroquine indicates that endosomal escape is not the limiting factor in this case, and it is shown, both experimentally and theoretically, that gene delivery can be correlated with the ability of the dendron assemblies to release DNA. Mass spectrometric assays demonstrate that the dendrons, as intended, do degrade under biologically relevant conditions over a period of hours. Multiscale modeling of degraded dendron structures suggests that complete dendron degradation would be required for DNA release. Importantly, in the presence of the lower pH associated with endosomes, or when bound to DNA, complete degradation of these dendrons becomes ineffective on the transfection time scale we propose this explains the poor transfection performance of these dendrons. As such, this paper demonstrates that taking this kind of multidisciplinary approach can yield a fundamental insight into the way in which dendrons can navigate barriers to cellular uptake. Lessons learned from this work will inform future dendron design for enhanced gene delivery.

  DOI：

  10.1021/ja2070736
• 作为产物：
  描述：

  2-((benzyloxy)carbonyl)-2-methylpropane-1,3-diyl bis(2-methyl-3-(((4-nitrophenoxy)carbonyl)oxy)-2-((((4-nitrophenoxy)carbonyl)oxy)methyl)propanoate) 、 tert-butyl (3-((3-aminopropyl)(methyl)amino)propyl)carbamate 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以87%的产率得到2-((benzyloxy)carbonyl)-2-methylpropane-1,3-diyl bis(2,2,9,17-tetramethyl-4,14-dioxo-17-(8,15,15-trimethyl-3,13-dioxo-2,14-dioxa-4,8,12-triazahexadecyl)-3,15-dioxa-5,9,13-triazaoctadecan-18-oate)
  参考文献：
  名称：

  Degradable Self-Assembling Dendrons for Gene Delivery: Experimental and Theoretical Insights into the Barriers to Cellular Uptake

  摘要：

  This paper uses a combined experimental and theoretical approach to gain unique insight into gene delivery. We report the synthesis and investigation of a new family of second-generation dendrons with four triamine surface ligands capable of binding to DNA, degradable aliphatic-ester dendritic scaffolds, and hydrophobic units at their focal points. Dendron self-assembly significantly enhances DNA binding as monitored by a range of experimental methods and confirmed by multiscale modeling. Cellular uptake studies indicate that some of these dendrons are highly effective at transporting DNA into cells (ca. 10 times better than poly(ethyleneimine), PEI). However, levels of transgene expression are relatively low (ca. 10% of PEI). This indicates that these dendrons cannot navigate all of the intracellular barriers to gene delivery. The addition of chloroquine indicates that endosomal escape is not the limiting factor in this case, and it is shown, both experimentally and theoretically, that gene delivery can be correlated with the ability of the dendron assemblies to release DNA. Mass spectrometric assays demonstrate that the dendrons, as intended, do degrade under biologically relevant conditions over a period of hours. Multiscale modeling of degraded dendron structures suggests that complete dendron degradation would be required for DNA release. Importantly, in the presence of the lower pH associated with endosomes, or when bound to DNA, complete degradation of these dendrons becomes ineffective on the transfection time scale we propose this explains the poor transfection performance of these dendrons. As such, this paper demonstrates that taking this kind of multidisciplinary approach can yield a fundamental insight into the way in which dendrons can navigate barriers to cellular uptake. Lessons learned from this work will inform future dendron design for enhanced gene delivery.

  DOI：

  10.1021/ja2070736