title: Specific targeting of telomeric multimeric G-quadruplexes by a new triaryl-substituted imidazole.
abstract: Multiple G-quadruplex units in the 3΄-terminal overhang of human telomeric DNA can associate and form multimeric structures. The specific targeting of such distinctive higher-order G-quadruplexes might be a promising strategy for developing selective anticancer agents with fewer side effects. However, thus far, only a few molecules were found to selectively bind to telomeric multimeric G-quadruplexes, and their effects on cancer cells were unknown. In this study, a new triaryl-substituted imidazole derivative called was synthesized and found to specifically bind to and strongly stabilize telomeric multimeric G-quadruplexes through intercalating into the pocket between the two quadruplex units. The pocket size might affect the binding behavior of . Further cellular studies indicated that could provoke cell cycle arrest, apoptosis and senescence in Siha cancer cells, mainly because of telomeric DNA damage and telomere dysfunction induced by the interactions of with telomeric G-quadruplexes. Notably, had no effect on the transcriptional levels of several common oncogenes that have the potential to form monomeric G-quadruplex structures in their promoter regions. Such behavior differed from that of traditional telomeric G-quadruplex ligands. Accordingly, this work provides new insights for the development of selective anticancer drugs targeting telomeric multimeric G-quadruplexes.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ming-Hao
authors.initials: MH
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Shuo-Bin
authors.initials: SB
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004249:DNA Damage / Q000187:drug effects; D054856:G-Quadruplexes; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology; D009857:Oncogenes / Q000235:genetics; D013057:Spectrum Analysis; D016615:Telomere / Q000737:chemistry* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D007093:Imidazoles; D009841:Oligonucleotides; C029899:imidazole; D004247:DNA