Innovative molecular platforms for G-quadruplex stabilization

Innovative molecular platforms for G-quadruplex stabilization S. Di Ciolo,a B. Airoldi,a L.C.M. Pariani,a C. F. Morelli,a C. Giannini,a A. Silvani,a D. Malpicci,a E. Cariati,a E. Lucenti,b C. Platella,c D. Musumeci,c R. Gaglione, c A. Arciello,c D. Montesarchioc aDipartimento di Chimica, Università degli studi di Milano, Milano bCNR-SCITEC, Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”, Milano cDipartimento di Scienze Chimiche, Università di Napoli Federico II, Napoli stefano.diciolo@unimi.it G-quadruplexes (G4s) have received considerable attention in recent years, due to evidence of their occurrence in living cells. 1Formed by stacks of guanine quartets, G4s belong to the wide class of non-canonical nucleic acid structures. Putative G4 forming sequences are distributed in genomic regions relevant for a number of pathologies, spanning from cancer to viral infections, where they can act as regulators of genetic information transfer.2 In this context, G4-targeting is regarded as a novel potential therapeutic approach for the treatment of associated diseases.3 Taking inspiration from the recent literature on G4 ligands4 and relying on the scaffold hopping strategy,5 we selected three different heterocyclic frameworks, potentially able to bind G4s by stacking the external G-tetrads. We functionalized these scaffolds with proper polar or positively charged flexible groups for binding to G4 loops/grooves, and/or with alkylating warheads for more selective covalent targeting. To investigate the G4 binding properties of the new molecules, in vitro biophysical studies were performed employing both telomeric and oncogene promoter G4-forming sequences. Interestingly, the investigated compounds showed potent G4-stabilizing properties and a certain preference for G4 over duplex DNA. Under preliminary in vitro studies, some ligands proved to inhibit cancer cells proliferation, not affecting healthy cells used as control. References: [1] S. Burge, G. N. Parkinson, P. Hazel, A. K. Todd, S. Neidle, Nucleic Acids Res. 2006, 34, 5402–5415. [2] R. Hänsel-Hertsch, M. Di Antonio, S. Balasubramanian, Nat. Rev. Mol. Cell Biol. 2017, 18, 279–284. [3] A. R. Duarte, E. Cadoni, A.S. Ressurreição, R. Moreira, A. Paulo ChemMedChem, 2018, 13, 869-893. [4] M. P. O'Hagan, J. C. Morales, M. C. Galan, Eur. J. Org. Chem. 2019, 4995–5017. [5] H. Sun,1, G. Tawa, A. Wallqvist Drug Discov Today. 2012 17(7-8), 310–324.