title: N-cyclic bay-substituted perylene G-quadruplex ligands have selective antiproliferative effects on cancer cells and induce telomere damage.
abstract: 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.
authors.affiliation: Dipartimento di Chimica, Università degli Studi La Sapienza, Ple A Moro 5, 00185 Roma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Casagrande
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.forename: Antonello
authors.initials: A
authors.lastname: Alvino
authors.forename: Armandodoriano
authors.initials: A
authors.lastname: Bianco
authors.forename: Alina
authors.initials: A
authors.lastname: Ciammaichella
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Luca
authors.initials: L
authors.lastname: Ginnari-Satriani
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Serrilli
authors.forename: Sara
authors.initials: S
authors.lastname: Iachettini
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Ortaggi
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.forename: Marco
authors.initials: M
authors.lastname: Franceschin
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010569:Perylene / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D008024:Ligands; C558508:N,N'-bis(5-(1-piperidino)-3-oxapentyl)-1,6-bis(1-piperidinyl)perylene-3,4,9,10-tetracarboxylic diimide; D010880:Piperidines; D010569:Perylene