Marco Franceschin1,2, Angela Rizzo3,2, Valentina Casagrande1, Erica Salvati3, Antonello Alvino1, Alessandro Altieri1, A Ciammaichella1, Sara Iachettini3, Carlo Leonetti3, Giancarlo Ortaggi1, Manuela Porru3, Armandodoriano Bianco4,5,1, Annamaria Biroccio4,5,3
1Dipartimento di Chimica, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma, Italy
2These authors contributed equally to the paper.
3Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome (Italy)
4Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome (Italy)
5Armandodoriano Bianco, Dipartimento di Chimica, Sapienza Università di Roma, P.le.A. Moro 5, 00185 Roma (Italy)
Tóm tắt
AbstractBased 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.
