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Dyads of G‐Quadruplex Ligands Triggering DNA Damage Response and Tumour Cell Growth Inhibition at Subnanomolar Concentration
Author(s) -
Doria Filippo,
Salvati Erica,
Pompili Luca,
Pirota Valentina,
D'Angelo Carmen,
Manoli Francesco,
Nadai Matteo,
Richter Sara N.,
Biroccio Annamaria,
Manet Ilse,
Freccero Mauro
Publication year - 2019
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.201900766
Subject(s) - linker , cytotoxicity , biophysics , chemistry , dna , g quadruplex , cell culture , dna damage , stereochemistry , biochemistry , biology , in vitro , genetics , computer science , operating system
Naphthalene diimide (NDI) dyads exhibiting a different substitution pattern and linker length have been synthesised and evaluated as G‐quadruplex (G4) ligands, by investigating their cytotoxicity in selected cell lines. The dyads with the long C 7 linker exhibit extremely low IC 50 values, below 10 n m , on different cancer cell lines. Contrary, the dyads with the shorter C 4 linker were much less effective, with IC values increasing up to 1 μ m . Among the three dyads with the longest linker, small differences in the IC 50 values emerge, suggesting that the linker length plays a more important role than the substitution pattern. We have further shown that the dyads are able to induce cellular DNA damage response, which is not limited to the telomeric regions and is likely the origin of their cytotoxicity. Both absorption titration and dynamic light scattering of the most cytotoxic dyads in the presence of hTel22 highlight their ability to induce effective G4 aggregation, acting as non‐covalent cross‐linking agents.