Benzo[ c ]acridine Dimer Cyclization as a Route toward a Small Bicationic Heteroaromatic Compound with Unprecedented G-Quadruplex Stabilization Properties
Abstract
G-quadruplex (G4) DNA structures are key regulatory elements in genome stability and gene expression, with a pronounced role in cancer biology due to their selective formation in oncogenic genomic regions and abundance in tumor cells. Their structural uniqueness makes them compelling targets for therapeutic intervention. Thus, targeting G4s with small molecule ligands offers a promising approach for modulating gene expression and inducing replication stress, particularly in DNA damage response-deficient malignancies such as ovarian and breast cancers. However, the structural diversity of G4s has hindered the development of ligands capable of broad-spectrum, topology-independent stabilization. Here, we introduce a novel dimeric N-methylbenzo[c]acridinium derivative, engineered as a visible-light-absorbing cationic G4 ligand. Compared to previously reported diazonia derivatives, this compound demonstrates red-shifted optical properties, superior luminescence quantum efficiency, and outstanding G4-stabilizing activity. It exhibits high preferential binding for G4s over dsDNA, induces conformational transitions between hybrid and antiparallel G4s, stalls DNA replication, and disrupts DNA duplex formation. Notably, its broad, topology-independent recognition enables stabilization of a range of G4 targets. Crucially, it surpasses benchmark G4 ligands, including PhenDC3 and CX-5461, in both selectivity and/or efficacy. These results support the dimeric benzo[c]acridinium scaffold as a versatile platform for the development of G4-targeted therapeutic strategies.
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BibTeX
@article{sandberg2026benzo,
title = {{Benzo[ c ]acridine Dimer Cyclization as a Route toward a Small Bicationic Heteroaromatic Compound with Unprecedented G-Quadruplex Stabilization Properties}},
author = {Stefanie Sandra Sandberg and Delphine Pitrat and Marine Labro and Sepideh Farmand Azadeh and Marco Deiana and Tangui Le Bahers and Sandrine Denis-Quanquin and Cyrille Monnereau and Natacha Gillet and Nasim Sabouri and Laure Guy},
journal = {ACS Chemical Biology},
year = {2026},
month = oct,
doi = {10.1021/acschembio.6c00586},
url = {https://hal.science/hal-05825131v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Benzo[ c ]acridine Dimer Cyclization as a Route toward a Small Bicationic Heteroaromatic Compound with Unprecedented G-Quadruplex Stabilization Properties
AU - Stefanie Sandra Sandberg
AU - Delphine Pitrat
AU - Marine Labro
AU - Sepideh Farmand Azadeh
AU - Marco Deiana
AU - Tangui Le Bahers
AU - Sandrine Denis-Quanquin
AU - Cyrille Monnereau
AU - Natacha Gillet
AU - Nasim Sabouri
AU - Laure Guy
PY - 2026
DA - 2026/10/15
JO - ACS Chemical Biology
DO - 10.1021/acschembio.6c00586
UR - https://hal.science/hal-05825131v1
AB - G-quadruplex (G4) DNA structures are key regulatory elements in genome stability and gene expression, with a pronounced role in cancer biology due to their selective formation in oncogenic genomic regions and abundance in tumor cells. Their structural uniqueness makes them compelling targets for therapeutic intervention. Thus, targeting G4s with small molecule ligands offers a promising approach for modulating gene expression and inducing replication stress, particularly in DNA damage response-deficient malignancies such as ovarian and breast cancers. However, the structural diversity of G4s has hindered the development of ligands capable of broad-spectrum, topology-independent stabilization. Here, we introduce a novel dimeric N-methylbenzo[c]acridinium derivative, engineered as a visible-light-absorbing cationic G4 ligand. Compared to previously reported diazonia derivatives, this compound demonstrates red-shifted optical properties, superior luminescence quantum efficiency, and outstanding G4-stabilizing activity. It exhibits high preferential binding for G4s over dsDNA, induces conformational transitions between hybrid and antiparallel G4s, stalls DNA replication, and disrupts DNA duplex formation. Notably, its broad, topology-independent recognition enables stabilization of a range of G4 targets. Crucially, it surpasses benchmark G4 ligands, including PhenDC3 and CX-5461, in both selectivity and/or efficacy. These results support the dimeric benzo[c]acridinium scaffold as a versatile platform for the development of G4-targeted therapeutic strategies.
SN - 1554-8929
SN - 1554-8937
ER -