Screening of Scaffolds for the Design of G-Quadruplex Ligands

In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) he...

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Bibliographic Details
Published in:Applied sciences 2022-02, Vol.12 (4), p.2170
Main Authors: Figueiredo, Joana, Peitinho, David, Campello, Maria Paula Cabral, Oliveira, Maria Cristina, Paulo, António, Mergny, Jean-Louis, Cruz, Carla
Format: Article
Language:English
Subjects:
Acridine
Aromatic compounds
Binding sites
Biochemistry, Molecular Biology
c-Myc protein
Cancer
Chromatography
Cytotoxicity
drug-design
Energy transfer
Fluorescence
Fluorescence resonance energy transfer
G-quadruplex
Gene expression
heterocycle compounds
Hydrocarbons
Life Sciences
Ligands
Myc protein
Naphthalene
Quinoline
Ribosomal DNA
Scaffolds
Selectivity
Solvents
Telomerase
Vascular endothelial growth factor
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Summary:In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) heterocycle compounds, containing different aromatic scaffolds, such as phenyl, quinoline, naphthalene, phenanthroline and acridine moieties, in order to explore their stabilization effect towards different DNA G4s, such as those found in c-MYC, KRAS21 and VEGF promoters, 21G human telomeric motif and pre-MIR150. The fluorescence resonance energy transfer (FRET) melting assay indicates that the acridine moiety is the most active scaffold, followed by phenanthroline. The different scaffolds are promising in terms of drug-like properties and, in general, the IC50 values of the respective heterocycle compounds are lower in a cancer cell line, when compared with a normal cell line. The acridine derivative C5NH2 has the most favorable cytotoxic profile in terms of cell selectivity.
ISSN:2076-3417
2076-3417
DOI:10.3390/app12042170