Quadruplex DNA-guided ligand selection from dynamic combinatorial libraries of acylhydrazones
Oksana Reznichenko1, Anne Cucchiarini1, Valérie Gabelica2
1CNRS UMR9187, Inserm U1196, Institut Curie, PSL Research University, 91405 Orsay, France. anton.granzhan@curie.fr and CNRS UMR9187, Inserm U1196, Université Paris Saclay, 91405 Orsay, France.
Organic & Biomolecular Chemistry
|December 16, 2020
Summary
Researchers developed novel acylhydrazone compounds using dynamic combinatorial chemistry. Two compounds showed strong binding affinity for G-quadruplex DNA structures, identified through magnetic bead pull-down assays.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Biochemistry
Background:
- G-quadruplex (G4) structures are unique nucleic acid motifs implicated in various biological processes.
- Developing small molecules that selectively bind to G4 structures is a key area in drug discovery.
- Dynamic combinatorial chemistry offers a powerful approach for generating diverse molecular libraries.
Purpose of the Study:
- To synthesize and identify novel acylhydrazone derivatives with potential G4-binding properties.
- To explore the utility of dynamic combinatorial libraries for discovering G4 ligands.
- To characterize the binding affinity and properties of identified G4 binders.
Main Methods:
- Preparation of dynamic combinatorial libraries of acylhydrazones using diacylhydrazides and aldehydes with a 5-methoxyanthranilic acid catalyst.
- Identification of potential G4 ligands via pull-down experiments using G4-oligonucleotide-functionalized magnetic beads.
- Resynthesis and structural emulation of identified ligands, followed by assessment of G4-binding properties using fluorimetric titrations, mass spectrometry, and thermal denaturation.
Main Results:
- Successful synthesis of dynamic combinatorial libraries of acylhydrazones.
- Identification of several putative G4-binding compounds through pull-down assays.
- Two novel acylhydrazone derivatives demonstrated strong binding affinity to G4 structures, with dissociation constants (Kd) less than 10 nM.
- Binding was confirmed through multiple biophysical techniques.
Conclusions:
- Dynamic combinatorial chemistry is an effective strategy for discovering G4 ligands.
- Novel acylhydrazone derivatives show significant potential as G4-targeting agents.
- These findings open avenues for developing new therapeutic strategies based on G4 modulation.
