title: 12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: a new class of highly selective ligands for c-myc G-quadruplex DNA.
abstract: 12-N-Methylated and non-methylated 5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized as new series of c-myc G-quadruplex binding ligands. Their interactions with c-myc G-quadruplex were evaluated using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), polymerase chain reaction (PCR) stop assay, and molecular modeling. Compared with the non-methylated derivatives, 12-N-methylated derivatives had stronger binding affinity and stabilizing ability to c-myc G-quadruplex structure, and could more effectively stack on the G-quartet surface. All these derivatives had high selectivity for c-myc G-quadruplex DNA over duplex DNA. The reverse transcription (RT) PCR assay showed that compound 21c could down-regulate transcription of c-myc gene in Ramos cell line containing NHE III(1) element, but had no effect in CA46 cell line with NHE III(1) element removed.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou University City, Waihuan East Road 132, Guangzhou 510006, People's Republic of China.
authors.forename: Sheng-Rong
authors.initials: SR
authors.lastname: Liao
authors.forename: Chen-Xi
authors.initials: CX
authors.lastname: Zhou
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Wu
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008745:Methylation; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013379:Substrate Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D044366:Transition Temperature
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D008024:Ligands; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA