Hammill Matthew L, Salim Lidya, Tsubaki Kouta, Varley Andrew J, Kitamura Mitsuru, Okauchi Tatsuo, Desaulniers Jean-Paul
Faculty of Science, University of Ontario Institute of Technology, 2000 Simcoe Street North, Oshawa, Ontario, L1G 0C5, Canada.
Department of Applied Chemistry, Graduate School of Engineering, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata, Kitakyushu, 804-8550, Japan.
Chembiochem. 2021 Oct 13;22(20):2981-2985. doi: 10.1002/cbic.202100334. Epub 2021 Aug 11.
Cubane molecules hold great potential for medicinal chemistry applications due to their inherent stability and low toxicity. In this study, we report the synthesis of a cubane derivative phosphoramidite for the incorporation of cubane into small interfering RNAs (siRNAs). Synthetic siRNAs rely on chemical modifications to improve their pharmacokinetic profiles. However, they are still able to mediate sequence-specific gene silencing via the endogenous RNA interference pathway. We designed a library of siRNAs bearing cubane at different positions within the sense and antisense strands. All siRNAs showed excellent gene-silencing activity, with IC values ranging from 45.4 to 305 pM. Incorporating the cubane modification in both the sense and antisense strand led to viable duplexes with good biological activity. To the best of our knowledge, this is the first report of siRNAs bearing a cubane derivative within the backbone.
立方烷分子因其固有的稳定性和低毒性，在药物化学应用中具有巨大潜力。在本研究中，我们报告了一种用于将立方烷掺入小干扰RNA（siRNA）的立方烷衍生物亚磷酰胺的合成。合成的siRNA依赖化学修饰来改善其药代动力学特性。然而，它们仍然能够通过内源性RNA干扰途径介导序列特异性基因沉默。我们设计了一个在正义链和反义链的不同位置带有立方烷的siRNA文库。所有siRNA均表现出优异的基因沉默活性，IC值范围为45.4至305 pM。在正义链和反义链中都引入立方烷修饰可产生具有良好生物活性的可行双链体。据我们所知，这是关于在主链中带有立方烷衍生物的siRNA的首次报道。
