title: Synthesis of bis-indole carboxamides as G-quadruplex stabilizing and inducing ligands.
abstract: The design and synthesis of a series of bis-indole carboxamides with varying amine containing side chains as G-quadruplex DNA stabilising small molecules are reported. Their interactions with quadruplexes have been evaluated by means of Förster resonance energy transfer (FRET) melting analysis, UV/Vis spectroscopy, circular dichroism spectroscopy and molecular modelling studies. FRET analysis indicates that these ligands exhibit significant selectivity for quadruplex over duplex DNA, and the position of the carboxamide side chains is of paramount importance in G-quadruplex stabilisation. UV/Vis titration studies reveal that bis-indole ligands bind tightly to quadruplexes and show a three- to fivefold preference for c-kit2 over h-telo quadruplex DNA. CD studies revealed that bis-indole carboxamide with a central pyridine ring induces the formation of a single, antiparallel, conformation of the h-telo quadruplex in the presence and absence of added salt. The chirality of h-telo quadruplex was transferred to the achiral ligand (induced CD) and the formation of a preferred atropisomer was observed.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. jyotidash@iiserkol.ac.in
authors.forename: Jyotirmayee
authors.initials: J
authors.lastname: Dash
authors.forename: Rabindra Nath
authors.initials: RN
authors.lastname: Das
authors.forename: Nagaratna
authors.initials: N
authors.lastname: Hegde
authors.forename: G Dan
authors.initials: GD
authors.lastname: Pantoş
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Shirude
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D054856:G-Quadruplexes / Q000187:drug effects*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D007211:Indoles; D008024:Ligands; D054852:Small Molecule Libraries; D004247:DNA