Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells |
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Authors: | Dr Eduarda Mendes Enrico Cadoni Filipa Carneiro Dr Marta B Afonso Hugo Brito Dr João Lavrado Dr Daniel J V A dos?Santos Dr Jorge B Vítor Prof Stephen Neidle Prof Cecília M P Rodrigues Prof Alexandra Paulo |
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Affiliation: | 1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649?003 Lisbon, Portugal;2. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649?003 Lisbon, Portugal
Department of Biochemistry & Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649?003 Lisbon, Portugal;3. School of Pharmacy, University College London, London, WC1N?1AX UK |
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Abstract: | 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. |
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Keywords: | cancer stem cells DNA drug design heterocycles G-quadruplexes |
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