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

Marco Franceschin, Angela Rizzo, Valentina Casagrande, Erica Salvati, Antonello Alvino, Alessandro Altieri, Alina Ciammaichella, Sara Iachettini, Carlo Leonetti, Giancarlo Ortaggi, Manuela Porru, Armandodoriano Bianco, Annamaria Biroccio

Research output: Contribution to journalArticlepeer-review

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 telomeres1 (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.

Original languageEnglish
Pages (from-to)2144-2154
Number of pages11
JournalChemMedChem
Volume7
Issue number12
DOIs
Publication statusPublished - Dec 2012

Keywords

  • Antitumor agents
  • Biological activity
  • Cancer
  • DNA damage
  • G-quadruplexes

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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