The Development of Potent DNA Triplex Binding Ligands by Expanding Aromatic Surface
Poster Number
24C
Introduction/Abstract
Triple helical DNA is a DNA structure in which three oligonucleotides wind around each other by forming Hoogsteen base pairs 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 antigene 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. Antigene 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 triple helical DNA while having minimal effect on the duplex DNA. Based on the previous findings, I have designed and synthesized novel quercetin derivatives by expanding aromatic surface areas.
Purpose
This work aims to design and synthesize novel quercetin derivatives by expanding aromatic surface areas. An increase in the surface area of a ligand is expected to give better π–π stacking interactions between the ligand and the nucleobases in triplex DNA, resulting in a more potent and specific triplex binding ligand.
Method
Different 5-substituded quercetin derivatives were synthesized. The compounds were purified using silica-gel column chromatography and then characterized by NMR, mass spectrometry, and IR. Thermal denaturation experiments monitored by UV were carried out to examine the stabilization of the triplexes by the ligands.
Results
Thermal denaturation experiments monitored by UV showed that two synthesized molecules have a much stronger binding effect on triplex DNA and RNA than previously developed ligands in the lab.
Significance
Antigene enhancers are small molecules facilitating triplex formation via intercalation or groove binding. The use of a TFO is a promising approach in antigene therapy because it can bind to a specific duplex DNA site and block the binding of nucleic acid processing enzymes in the same region.
Location
Library and Learning Center, 3601 Pacific Ave., Stockton, CA 95211
Format
Poster Presentation
The Development of Potent DNA Triplex Binding Ligands by Expanding Aromatic Surface
Library and Learning Center, 3601 Pacific Ave., Stockton, CA 95211
Triple helical DNA is a DNA structure in which three oligonucleotides wind around each other by forming Hoogsteen base pairs 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 antigene 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. Antigene 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 triple helical DNA while having minimal effect on the duplex DNA. Based on the previous findings, I have designed and synthesized novel quercetin derivatives by expanding aromatic surface areas.
