title: Aromatic core extension in the series of N-cyclic bay-substituted perylene G-quadruplex ligands: increased telomere damage, antitumor activity, and strong selectivity for neoplastic over healthy cells.
abstract: Based on previous work on both perylene and coronene derivatives as G-quadruplex binders, a novel chimeric compound was designed: N,N'-bis[2-(1-piperidino)-ethyl]-1-(1-piperidinyl)-6-[2-(1-piperidino)-ethyl]-benzo[ghi]perylene-3,4:9,10-tetracarboxylic diimide (EMICORON), having one piperidinyl group bound to the perylene bay area (positions 1, 12 and 6, 7 of the aromatic core), sufficient to guarantee good selectivity, and an extended aromatic core able to increase the stacking interactions with the terminal tetrad of the G-quadruplex. The obtained "chimera" molecule, EMICORON, rapidly triggers extensive DNA damage of telomeres, associated with the delocalization of telomeric protein protection of telomeres 1 (POT1), and efficiently limits the growth of both telomerase-positive and -negative tumor cells. Notably, the biological effects of EMICORON are more potent than those of the previously described perylene derivative (PPL3C), and more interestingly, EMICORON appears to be detrimental to transformed and tumor cells, while normal fibroblasts expressing telomerase remain unaffected. These results identify a new promising G-quadruplex ligand, structurally and biologically similar on one side to coronene and on the other side to a bay-monosubstituted perylene, that warrants further studies.
authors.affiliation: Dipartimento di Chimica, Sapienza Università di Roma, P.le.A. Moro 5, 00185 Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Franceschin
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
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: Alessandro
authors.initials: A
authors.lastname: Altieri
authors.forename: Alina
authors.initials: A
authors.lastname: Ciammaichella
authors.forename: Sara
authors.initials: S
authors.lastname: Iachettini
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Ortaggi
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.forename: Armandodoriano
authors.initials: A
authors.lastname: Bianco
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D016615:Telomere / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D011083:Polycyclic Compounds; D010569:Perylene; C012256:coronene