Combining 1,3‐Ditriazolylbenzene and Quinoline to Discover a New G‐Quadruplex‐Interactive Small Molecule Active against Cancer Stem‐Like Cells

Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment‐based approach to create new flexible G‐quadruplex (G4) DNA‐interactive small molecules with good calculated oral drug‐like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)‐stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose‐ and DNA sequence‐dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G‐quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4′‐(4,4′‐(1,3‐phenylene)bis(1H‐1,2,3‐triazole‐4,1‐diyl))bis(1‐methylquinolin‐1‐ium) (1 d) showed the greater activity. Importantly, dose–response curves show that 1 d is cytotoxic in the human colon cancer HT‐29 cell line enriched in cancer stem‐like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells.

Eduarda Mendes a, Enrico Cadoni a, Filipa Carneiro a, Marta B. Afonso a, Hugo Brito a, João Lavrado a, Daniel J. V. A. dos Santos a, Jorge B. Vítor a,b, Stephen Neidle c, Cecília M. P. Rodrigues a, Alexandra Paulo a*

a Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649 003 Lisbon, PortugalE-mail:

b Department of Biochemistry & Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal

c School of Pharmacy, UCL, London WC1N 1

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