[1-[3-[[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonylamino]propyl]triazol-4-yl]methyl 3-[3-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxy]-2-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxymethyl]-2-methylpropanoyl]oxy-2-[[3-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxy]-2-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxymethyl]-2-methylpropanoyl]oxymethyl]-2-methylpropanoate | 1355319-93-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: [1-[3-[[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonylamino]propyl]triazol-4-yl]methyl 3-[3-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxy]-2-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxymethyl]-2-methylpropanoyl]oxy-2-[[3-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxy]-2-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxymethyl]-2-methylpropanoyl]oxymethyl]-2-methylpropanoate
• CAS: 1355319-93-5
• 化学式: C₈₁H₁₄₈N₁₆O₁₆
• 分子量: 1602.16
• InChiKey: CHMUKJAENQHFRO-AXMGPCHQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  113
• 可旋转键数：
  63
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  418
• 氢给体数：
  9
• 氢受体数：
  26

反应信息

• 作为产物：
  描述：

  在 盐酸 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以98%的产率得到[1-[3-[[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxycarbonylamino]propyl]triazol-4-yl]methyl 3-[3-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxy]-2-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxymethyl]-2-methylpropanoyl]oxy-2-[[3-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxy]-2-[3-[3-aminopropyl(methyl)amino]propylcarbamoyloxymethyl]-2-methylpropanoyl]oxymethyl]-2-methylpropanoate
  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

文献信息

• Degradable Self-Assembling Dendrons for Gene Delivery: Experimental and Theoretical Insights into the Barriers to Cellular Uptake
  作者：Anna Barnard、Paola Posocco、Sabrina Pricl、Marcelo Calderon、Rainer Haag、Mark E. Hwang、Victor W. T. Shum、Daniel W. Pack、David K. Smith

  DOI：10.1021/ja2070736

  日期：2011.12.21

  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.