Development of Potent DNA Triplex Binding Ligands by Expanding Aromatic Surface

Triple helical DNA is a DNA structure in which three oligonucleotides wind around each other by forming Hoogsteen base pairs either intra- or intermolecularly. Intramolecular triplex DNA (H-DNA) is formed in supercoiled DNAs with homopurine and homopyrimidine strands with mirror repeat symmetry. Intermolecular triplex occurs between a duplex and a neighboring chromosome or a triplex-forming oligonucleotide (TFO). The use of a TFO is promising in anti-gene therapy because it will bind to a targeted duplex DNA site in a sequence-specific manner. However, the association of a TFO with a duplex is thermodynamically less favorable and kinetically slower than its counterpart duplex formation. Anti-gene enhancers are small molecules that can facilitate triplex formation via intercalation or groove binding. Our research group has recently discovered two novel quercetin derivatives that show strong binding toward the triplex while having minimal effect on the duplex DNA