title: Structure-based design of flavone derivatives as c-myc oncogene down-regulators.
abstract: Based on molecular docking analysis of complexes between flavone and the c-myc G-quadruplex, we designed and screened 30 flavone derivatives containing various side chains that could potentially form interactions with the G-quadruplex grooves. As a proof-of-concept, the highest-scoring flavone derivatives containing cationic pyridinium side chains were synthesized and their interactions with the c-myc G-quadruplex were examined using a PCR-stop assay. The stabilizing effects of the flavone derivatives were found to be selective towards the c-myc G-quadruplex over other biologically relevant G-quadruplex structures, such as the human telomeric sequence (HTS). The interaction between the most potent compound of the series and the c-myc G-quadruplex was examined in depth using UV-Vis titration, molecular modeling and CD spectroscopy. Our results suggest that in addition to stabilizing the c-myc G-quadruplex, the flavone derivatives were capable of inducing the formation of the G-quadruplex structure even in the absence of monovalent cations. The flavone derivatives were found to be potent inhibitors of c-myc promoters within the cellular environment and displayed promising cytotoxic behavior against human cancer cell lines.
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Zhong
authors.forename: Ka-Ho
authors.initials: KH
authors.lastname: Leung
authors.forename: Daniel Shiu-Hin
authors.initials: DS
authors.lastname: Chan
authors.forename: Victor Pui-Yan
authors.initials: VP
authors.lastname: Ma
authors.forename: Wai-Chung
authors.initials: WC
authors.lastname: Fu
authors.forename: Rupesh
authors.initials: R
authors.lastname: Nanjunda
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.forename: Chung-Hang
authors.initials: CH
authors.lastname: Leung
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D015536:Down-Regulation / Q000187:drug effects; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D054856:G-Quadruplexes; D016259:Genes, myc; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011401:Promoter Regions, Genetic
chemical_list: D047309:Flavones