title: Targeting DNA G-quadruplexes with helical small molecules.
abstract: We previously identified quinoline-based oligoamide helical foldamers and a trimeric macrocycle as selective ligands of DNA quadruplexes. Their helical structures might permit targeting of the backbone loops and grooves of G-quadruplexes instead of the G-tetrads. Given the vast array of morphologies G-quadruplex structures can adopt, this might be a way to achieve sequence selective binding. Here, we describe the design and synthesis of molecules based on macrocyclic and helically folded oligoamides. We tested their ability to interact with the human telomeric G-quadruplex and an array of promoter G-quadruplexes by using FRET melting assay and single-molecule FRET. Our results show that they constitute very potent ligands--comparable to the best so far reported. Their modes of interaction differ from those of traditional tetrad binders, thus opening avenues for the development of molecules specific for certain G-quadruplex conformations.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK); Cambridge Institute, Cancer Research UK, Li Ka Shing Center, Cambridge CB2 0RE (UK).
authors.forename: Sebastian
authors.initials: S
authors.lastname: Müller
authors.forename: Katta
authors.initials: K
authors.lastname: Laxmi-Reddy
authors.forename: Prakrit V
authors.initials: PV
authors.lastname: Jena
authors.forename: Benoit
authors.initials: B
authors.lastname: Baptiste
authors.forename: Zeyuan
authors.initials: Z
authors.lastname: Dong
authors.forename: Frédéric
authors.initials: F
authors.lastname: Godde
authors.forename: Taekjip
authors.initials: T
authors.lastname: Ha
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Ivan
authors.initials: I
authors.lastname: Huc
mesh_terms: D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes / Q000187:drug effects*; D008024:Ligands; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008024:Ligands; D015363:Quinolones; D054852:Small Molecule Libraries
keywords: DNA structures; FRET; G-quadruplex; foldamers; single-molecule fluorescence