A series of amino- and guanidino-terminating 3- and 4-generation 2,4-diaminobutanoic acid (Dab) dendrons have been robustly synthesized on a solid phase and characterized as cellular delivery agents in antisense peptide nucleic acid (PNA) conjugates in the pLuc705 HeLa cell splice switching system. The dendron-PNA conjugates exhibited splice correction activity at one digit micromolar concentrations, and guanidino-terminating dendrons were significantly more effective than analogous amine terminating ones. Furthermore, introduction of lipophilic groups such as phenyl, alkyl, or fatty acids increased efficacy, but also increased cellular toxicity. Fluorescence microscopy analyses supported an endosomal uptake mechanism and furthermore predominantly showed colocalization with late endosomes and lysosomes. The robust solid phase synthesis should make such Dab-dendrons a useful platform for further in vitro as well as in vivo optimization.

中文翻译：

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通过与基于胍基酰化的二氨基丁酸的肽树突结合而有效的细胞反义肽核酸的细胞递送。

已在固相上稳健地合成了一系列氨基和胍基终止的3和4代2,4-二氨基丁酸（Dab）树突，并将其表征为反义肽核酸（PNA）缀合物中的细胞递送剂。 pLuc705 HeLa细胞拼接开关系统。Dendron-PNA共轭物在一位数的微摩尔浓度下表现出剪接校正活性，并且端胍基树突比类似胺端基的树突明显更有效。此外，亲脂性基团如苯基，烷基或脂肪酸的引入增加了功效，但也增加了细胞毒性。荧光显微镜分析支持内体摄取机制，并且主要显示与晚期内体和溶酶体共定位。