Mendes, E;
Cadoni, E;
Carneiro, F;
Afonso, MB;
Brito, H;
Lavrado, J;
dos Santos, DJVA;
... Paulo, A; + view all
(2019)
Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells.
ChemMedChem
, 14
(14)
pp. 1325-1328.
10.1002/cmdc.201900243.
Preview |
Text
Neidle_Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells_AAM.pdf - Accepted Version Download (691kB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/cmdc.201900243 |
| Publisher version: | https://doi.org/10.1002/cmdc.201900243 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | cancer stem cells, DNA, drug design, heterocycles, G-quadruplexes |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10096355 |
Archive Staff Only
 |
View Item |
