Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona Martí i Franquès 1-11, E-08028 Barcelona, Spain.
J Org Chem. 2013 Nov 1;78(21):10666-77. doi: 10.1021/jo401684j. Epub 2013 Oct 16.
The design and synthesis of two Janus-type heterocycles with the capacity to simultaneously recognize guanine and uracyl in G-U mismatched pairs through complementary hydrogen bond pairing is described. Both compounds were conveniently functionalized with a carboxylic function and efficiently attached to a tripeptide sequence by using solid-phase methodologies. Ligands based on the derivatization of such Janus compounds with a small aminoglycoside, neamine, and its guanidinylated analogue have been synthesized, and their interaction with Tau RNA has been investigated by using several biophysical techniques, including UV-monitored melting curves, fluorescence titration experiments, and (1)H NMR. The overall results indicated that Janus-neamine/guanidinoneamine showed some preference for the +3 mutated RNA sequence associated with the development of some tauopathies, although preliminary NMR studies have not confirmed binding to G-U pairs. Moreover, a good correlation has been found between the RNA binding affinity of such Janus-containing ligands and their ability to stabilize this secondary structure upon complexation.
描述了两种具有同时识别鸟嘌呤和尿嘧啶在 G-U 错配碱基对的能力的 Janus 型杂环的设计和合成。这两种化合物都方便地进行了羧酸官能化，并通过固相方法有效地连接到三肽序列上。基于此类 Janus 化合物与小的氨基糖苷 neamine 的衍生化及其胍基化类似物的配体已被合成，并通过多种生物物理技术研究了它们与 Tau RNA 的相互作用，包括 UV 监测的熔点曲线、荧光滴定实验和（1）H NMR。总体结果表明，Janus-neamine/guanidinoneamine 对与一些 tau 病发展相关的 +3 突变 RNA 序列表现出一定的偏好，尽管初步的 NMR 研究尚未证实与 G-U 对的结合。此外，还发现这种含 Janus 的配体的 RNA 结合亲和力与其在复合物形成时稳定这种二级结构的能力之间存在良好的相关性。
