Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 2K6.
J Am Chem Soc. 2011 Feb 2;133(4):728-31. doi: 10.1021/ja109817p. Epub 2010 Dec 20.
It is controversial whether organic fluorine can form energetically important hydrogen bonds in aqueous environments. We previously showed by NMR and molecular modeling that the unexpectedly high binding affinity of 2'F-ANA is largely due to a C-H···F-C pseudohydrogen bond at pyrimidine-purine steps. Comparisons of the melting of duplexes with identical sequence composition but a rearranged sequence confirm that energetically important fluorine-mediated pseudohydrogen bonding is in operation in these sequences. The effect is of particular importance when the H-bond donor (purine H8) is activated by the presence of fluorine at its own 2'-position. These results provide a rational method to increase the binding affinity of antisense oligonucleotides by placement of 2'F-ANA modifications at pyrimidine-purine steps.
有机氟是否能在水相环境中形成能量重要的氢键存在争议。我们之前通过 NMR 和分子建模表明，2'F-ANA 出人意料的高结合亲和力主要归因于嘧啶-嘌呤碱基对上的 C-H···F-C 伪氢键。对具有相同序列组成但序列排列不同的双链体的熔解进行比较，证实了在这些序列中存在能量重要的氟介导的伪氢键作用。当氢键供体（嘌呤 H8）被其自身 2'-位的氟激活时，这种效应尤其重要。这些结果为通过在嘧啶-嘌呤碱基对处放置 2'F-ANA 修饰来提高反义寡核苷酸的结合亲和力提供了一种合理的方法。
