The telomeric 3'-overhang had potential to form into higher-order structures termed multimeric G-quadruplexes (G4s), which may mainly exist in telomeres, representing an attractive drug target for development of anticancer agents with few side effects. However, only a few molecules that selectively bind to multimeric G4s have been found by random screening, which means a lot of room for improvement. In this study, we raised a feasible strategy to design small-molecule ligands with possible selectivity to multimeric G4s, and then synthesized a focused library of multi-aryl compounds by attaching triazole rings to the quinoxaline skeleton. Among them, QTR-3 was identified as the most promising selective ligand that may bind at the G4-G4 interface, which accordingly stabilized multimeric G4s and induced DNA damage in telomeric region, thereby leading to cell cycle arrest and apoptosis. Notably, QTR-3 showed more significant inhibition on breast cancer cells against normal mammary cells.
Keywords: Breast cancer; Multimeric G-quadruplex; Selective; Telomere; Triazole.
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