Synthesis of Janus Compounds for the Recognition of G-U Mismatched Nucleobase Pairs

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 guanidinylated analogue have been synthesized, and their interaction with such Janus compounds with a small aminoglycoside, neamine, and its Tau RNA has been investigated by using several biophysical techniques, including including UV-monitored melting curves, fluorescence titration experiments, and H-1 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.