Combining the Best in Triplex Recognition:  Synthesis and Nucleic Acid Binding of a BQQ−Neomycin Conjugate

Synthesis of a BQQ−neomycin conjugate is reported. The conjugate combines two ligands, one known to intercalate triplexes (BQQ) and another known to bind in the triplex groove (neomycin). The conjugate stabilizes T·A·T, as well as mixed base DNA triplex, better than neomycin, BQQ, or a combination of both. The conjugate selectively stabilizes the triplex (in the presence of physiological salt concentrations), with as little as 4 μM of the ligand leading to a ΔT_m of >60 °C. Competition dialysis studies show a clear preference for the drug binding to triplex DNA/RNA over the duplex/single strand structures. Modeling studies suggest a structure of neomycin bound to the larger W−H (Watson−Hoogsteen) groove with BQQ intercalated between the triplex bases.