Identification of Effective Anticancer G-Quadruplex-Targeting Chemotypes through the Exploration of a High Diversity Library of Natural Compounds
Chiara Platella,
Francesca Ghirga,
Pasquale Zizza,
Luca Pompili,
Simona Marzano,
Bruno Pagano,
Deborah Quaglio,
Valeria Vergine,
Silvia Cammarone,
Bruno Botta,
Annamaria Biroccio,
Mattia Mori,
Daniela Montesarchio
Affiliations
Chiara Platella
Department of Chemical Sciences, University of Naples Federico II (Complesso Universitario di Monte S. Angelo), Via Cintia, 21, 80126 Napoli, Italy
Francesca Ghirga
Department of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Pasquale Zizza
Oncogenomic and Epigenetic Unit, IRCCS—Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
Luca Pompili
Oncogenomic and Epigenetic Unit, IRCCS—Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
Simona Marzano
Department of Pharmacy, “Department of Excellence 2018−2022”, University of Naples Federico II, Via D.Montesano, 49, 80131 Napoli, Italy
Bruno Pagano
Department of Pharmacy, “Department of Excellence 2018−2022”, University of Naples Federico II, Via D.Montesano, 49, 80131 Napoli, Italy
Deborah Quaglio
Department of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Valeria Vergine
Department of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Silvia Cammarone
Department of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Bruno Botta
Department of Chemistry and Technology of Drugs, “Department of Excellence 2018−2022”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Annamaria Biroccio
Oncogenomic and Epigenetic Unit, IRCCS—Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
Mattia Mori
Department of Biotechnology, Chemistry and Pharmacy, “Department of Excellence 2018-2022”, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Daniela Montesarchio
Department of Chemical Sciences, University of Naples Federico II (Complesso Universitario di Monte S. Angelo), Via Cintia, 21, 80126 Napoli, Italy
In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural compounds have been thus far poorly explored, though representing appealing candidates due to the high structural diversity of their scaffolds. In this regard, a unique high diversity in-house library composed of ca. one thousand individual natural products was investigated. The combination of molecular docking-based virtual screening and the G4-CPG experimental screening assay proved to be useful to quickly and effectively identify—out of many natural compounds—five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously demonstrated the selective interaction of these compounds with G4s compared to duplex DNA. The rationale behind the G4 selective recognition was suggested by molecular dynamics simulations. Indeed, the selected ligands proved to specifically interact with G4 structures due to peculiar interaction patterns, while they were unable to firmly bind to a DNA duplex. From biological assays, Chelidonine and Rotenone emerged as the most active compounds of the series against cancer cells, also showing good selectivity over normal cells. Notably, the anticancer activity correlated well with the ability of the two compounds to target telomeric G4s.
