TY - JOUR
T1 - N-cyclic bay-substituted perylene g-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage
AU - Casagrande, Valentina
AU - Salvati, Erica
AU - Alvino, Antonello
AU - Bianco, Armandodoriano
AU - Ciammaichella, Alina
AU - D'Angelo, Carmen
AU - Ginnari-Satriani, Luca
AU - Serrilli, Anna Maria
AU - Iachettini, Sara
AU - Leonetti, Carlo
AU - Neidle, Stephen
AU - Ortaggi, Giancarlo
AU - Porru, Manuela
AU - Rizzo, Angela
AU - Franceschin, Marco
AU - Biroccio, Annamaria
PY - 2011/3/10
Y1 - 2011/3/10
N2 - A series of bay-substituted perylene derivatives is reported as a new class of G-quadruplex ligands. The synthesized compounds have differing N-cyclic substituents on the bay area and differing side chains on the perylene major axis. ESI-MS and FRET measurements highlighted the strongest quadruplex binders in this series and those showing the highest quadruplex/duplex selectivity. Several biological assays were performed on these compounds, which showed that compound 5 (PPL3C) triggered a DNA damage response in transformed cells with the formation of telomeric foci containing phosphorylated γ-H2AX and 53BP1. This effect mainly occurred in replicating cells and was consistent with Pot1 dissociation. Compound 5 does not induce telomere damage in normal cells, which are unaffected by treatment with the compound, suggesting that this agent preferentially kills cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs.
AB - A series of bay-substituted perylene derivatives is reported as a new class of G-quadruplex ligands. The synthesized compounds have differing N-cyclic substituents on the bay area and differing side chains on the perylene major axis. ESI-MS and FRET measurements highlighted the strongest quadruplex binders in this series and those showing the highest quadruplex/duplex selectivity. Several biological assays were performed on these compounds, which showed that compound 5 (PPL3C) triggered a DNA damage response in transformed cells with the formation of telomeric foci containing phosphorylated γ-H2AX and 53BP1. This effect mainly occurred in replicating cells and was consistent with Pot1 dissociation. Compound 5 does not induce telomere damage in normal cells, which are unaffected by treatment with the compound, suggesting that this agent preferentially kills cancer cells. These results reinforce the notion that G-quadruplex binding compounds can act as broad inhibitors of telomere-related processes and have potential as selective antineoplastic drugs.
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U2 - 10.1021/jm1013665
DO - 10.1021/jm1013665
M3 - Article
C2 - 21280624
AN - SCOPUS:79952260703
VL - 54
SP - 1140
EP - 1156
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -