title: 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.
abstract: 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 (ΔT(m)) than the other three compounds and also gives 80.2% inhibition of telomerase activity at 7.5 μM. 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(-5) M, respectively, and cause a substantial decrease in the G2/M-phase cell population and a significant increase in the number of apoptotic cells.
authors.affiliation: Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, PR China. weichuny@sxu.edu.cn
authors.forename: Chun-Ying
authors.initials: CY
authors.lastname: Wei
authors.forename: Jun-Hong
authors.initials: JH
authors.lastname: Wang
authors.forename: Ye
authors.initials: Y
authors.lastname: Wen
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D054856:G-Quadruplexes; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D009691:Nucleic Acid Denaturation; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D004791:Enzyme Inhibitors; C489427:MYC protein, human; D010618:Phenanthrolines; D010636:Phenols; D016271:Proto-Oncogene Proteins c-myc; D019009:Proto-Oncogene Proteins c-kit; D019098:Telomerase