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Photoactivatable V‐Shaped Bifunctional Quinone Methide Precursors as a New Class of Selective G‐quadruplex Alkylating Agents
Author(s) -
Lena Alberto,
Benassi Alessandra,
Stasi Michele,
SaintPierre Christine,
Freccero Mauro,
Gasparutto Didier,
Bombard Sophie,
Doria Filippo,
Verga Daniela
Publication year - 2022
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202200734
Subject(s) - bifunctional , quinone methide , chemistry , covalent bond , adduct , ligand (biochemistry) , quinone , combinatorial chemistry , stereochemistry , selectivity , biochemistry , receptor , organic chemistry , catalysis
Combining the selectivity of G‐quadruplex (G4) ligands with the spatial and temporal control of photochemistry is an emerging strategy to elucidate the biological relevance of these structures. In this work, we developed six novel V‐shaped G4 ligands that can, upon irradiation, form stable covalent adducts with G4 structures via the reactive intermediate, quinone methide (QM). We thoroughly investigated the photochemical properties of the ligands and their ability to generate QMs. Subsequently, we analyzed their specificity for various topologies of G4 and discovered a preferential binding towards the human telomeric sequence. Finally, we tested the ligand ability to act as photochemical alkylating agents, identifying the covalent adducts with G4 structures. This work introduces a novel molecular tool in the chemical biology toolkit for G4s.