4-(1H-Imidazo[4,5-f]-1,10-phenanthrolin-2-yl)phenol-based G-quadruplex DNA binding agents: Telomerase inhibition, cytotoxicity and DNA-binding studies
2013
Wei, Chun-Ying | Wang, Jun-Hong | Wen, Ye | Liu, Jie | Wang, Li-Hua
Four novel 4-(1H-imidazo[4,5-f]-1,10-phenanthrolin-2-yl)phenol derivatives 1–4 have been synthesized, and their G-quadruplex DNA-binding interactions, telomerase inhibition, antiproliferative activity, cell cycle arrest, and apoptotic induction were studied. All compounds show the preferential h-telo, c-myc, and c-kit2 G-quadruplex binding affinity and the G-quadruplex versus duplex selectivity. In the case of the same G-quadruplex target, the compound 1 exhibits better stabilization effect (ΔTₘ) than the other three compounds and also gives 80.2% inhibition of telomerase activity at 7.5μM. All compounds can promote selectively the formation of parallel G-quadruplex structure of both c-myc and c-kit2 without addition of any cations. Four compounds display the cytotoxicity activities against HeLa and HepG2 cells by MTT assay with IC₅₀ values of about 10⁻⁶ and 10⁻⁵M, respectively, and cause a substantial decrease in the G₂/M-phase cell population and a significant increase in the number of apoptotic cells.
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