Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Profesor García González 1, E-41012 Sevilla, Spain.
J Org Chem. 2011 Aug 5;76(15):5882-94. doi: 10.1021/jo2007785. Epub 2011 Jul 6.
Monodisperse facial amphiphiles consisting of a β-cyclodextrin (βCD) platform exposing a multivalent display of cationic groups at the primary rim and bearing hydrophobic chains at the secondary oxygens have been prepared by implementing two very robust "click" methodologies, namely cuprous cation-catalyzed azide-alkyne cycloaddition (CuAAC) and thiourea-forming reaction. Most interestingly, the use of solid-supported Cu(I) catalysts was found to be very well suited for multiple CuAAC while facilitating purification of the C(7)-symmetric macromolecular triazole adducts. The strategy is compatible with molecular diversity-oriented approaches, which has been exploited to generate a small library of click polycationic amphiphilic CDs (paCDs) for assessing the influence of structural modifications in the ability to complex, compact, and protect pDNA and the efficiency of the resulting paCD:pDNA nanocomplexes (CDplexes) to deliver DNA into cells and promote transfection. The results indicate that fine-tuning the hydrophilic/hydrophobic balance is critical to achieve optimal self-assembling properties and stability of the resulting CDplexes in saline- and serum-containing media. Triazole-type paCDs were, in general, less efficient in promoting gene transfection than thiourea-type derivatives. Nevertheless, the current body of results support that the "dual click" approach implying sequential CuAAC and thiourea-forming reactions represents a versatile strategy to optimize the gene delivery capabilities of cyclodextrin-based facial amphiphiles.
已经通过实施两种非常稳健的“点击”方法，即铜催化的叠氮-炔环加成（CuAAC）和硫脲形成反应，制备了由β-环糊精（βCD）平台组成的单分散面型两亲物，该平台在主边缘上暴露了多价的阳离子基团，并在次级氧上带有疏水链。最有趣的是，发现使用固载的 Cu(I)催化剂非常适合多次 CuAAC，同时有利于 C(7)-对称的大分子三唑加合物的纯化。该策略与分子多样性导向的方法兼容，已被用于生成点击聚阳离子两亲性 CD（paCD）的小文库，以评估结构修饰对与 pDNA 络合、压缩和保护的能力的影响，以及所得 paCD:pDNA 纳米复合物（CDplex）将 DNA 递送到细胞中并促进转染的效率。结果表明，精细调整亲水/疏水平衡对于在盐和含血清的介质中实现最佳的自组装性能和所得 CDplex 的稳定性至关重要。一般来说，三唑型 paCD 促进基因转染的效率不如硫脲型衍生物。然而，目前的结果表明，涉及顺序 CuAAC 和硫脲形成反应的“双重点击”方法代表了优化基于环糊精的面型两亲物的基因传递能力的一种通用策略。
