title: Disubstituted 1,8-dipyrazolcarbazole derivatives as a new type of c-myc G-quadruplex binding ligands.
abstract: A series of 1,8-dipyrazolcarbazole (DPC) derivatives (6a-6d, 7a-7d) designed as G-quadruplex ligands have been synthesized and characterized. The FRET-melting and SPR results showed that the DPC derivatives could well recognize G-quadruplex with strong discrimination against the duplex DNA. In addition, the DPC derivatives showed much stronger stabilization activities and binding affinities for c-myc G-quadruplex rather than telomeric G-quadruplex. Therefore, their interactions with c-myc G-quadruplex were further explored by means of CD spectroscopy, PCR-stop assay, and molecular modeling. In cellular studies, all compounds showed strong cytotoxicity against cancer cells, while weak cytotoxicity towards normal cells. RT-PCR assay showed that compound 7b could down-regulate c-myc gene expression in Ramos cell line, while had no effect on c-myc expression in CA46 cell line with NHE III(1) element removed, indicating its effective binding with G-quadruplex on c-myc oncogene in vivo.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Chen
authors.forename: Chen-Xi
authors.initials: CX
authors.lastname: Zhou
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Yao
authors.forename: Xiao-Xiao
authors.initials: XX
authors.lastname: Wang
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D015536:Down-Regulation; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D018922:HL-60 Cells; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D002227:Carbazoles; D008024:Ligands; D016271:Proto-Oncogene Proteins c-myc; C041514:carbazole