The Development of Potent DNA Triplex Binding Ligands by Expanding The Aromatic Surface
Poster Number
19B
Research or Creativity Area
Pharmacy
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 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 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. An increase in the surface area of a ligand should 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. Twenty-one novel quercetin derivatives have been synthesized and characterized by NMR, MS, and IR. In this presentation, I will discuss the synthesis protocols of the derivatives and the evaluation of their binding to triplex DNA using thermal denaturation monitored by UV.
Purpose
This work aimed to design and synthesize novel quercetin derivatives by expanding aromatic surface areas. An increase in the surface area of a ligand was 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.
Results
Thermal denaturation experiments monitored by UV showed that ligands containing C3 linkers stabilize triplex DNA slightly better than those with C4 and C2 linkers. Many of these newly synthesized ligands exhibit a transition from triplex to single-stranded DNA. These ligands have a much stronger binding effect on triplex DNA than previously developed ligands in the lab.
Significance
Anti-gene enhancers are small molecules that can facilitate triplex formation via intercalation or groove binding. The use of a TFO is a promising approach in anti-gene 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
Don and Karen DeRosa University Center (DUC) Poster Hall
Start Date
27-4-2024 10:30 AM
End Date
27-4-2024 12:30 PM
The Development of Potent DNA Triplex Binding Ligands by Expanding The Aromatic Surface
Don and Karen DeRosa University Center (DUC) Poster Hall
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 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 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. An increase in the surface area of a ligand should 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. Twenty-one novel quercetin derivatives have been synthesized and characterized by NMR, MS, and IR. In this presentation, I will discuss the synthesis protocols of the derivatives and the evaluation of their binding to triplex DNA using thermal denaturation monitored by UV.
