title: Study of the interaction between indole-based compounds and biologically relevant G-quadruplexes.
abstract: G-quadruplexes (G4s) are high-order secondary structures that modulate several key cell processes such as telomere function, gene expression and DNA replication. In the past years G4s have emerged as promising targets for drug development due to the discovery of small molecules which bind and stabilize these structures. In this work, we report the synthesis of indole-based compounds and the study of their interaction with the biological relevant G4s c-MYC and human telomeric repeat 22AG using several biophysical techniques. The ligands are G4 specific and they can discriminate different G4 structures namely parallel and hybrid-1 topologies. The NMR study of interaction between the most promising indole-derivative (compound 3) and c-MYC quadruplex suggests that the ligand binds on the external tetrads with additional actions in the loops/grooves in a 2:1 ratio. The molecular docking calculations of compound 3 to c-MYC quadruplex corroborates with the1H and NOESY NMR studies. Overall, the results suggest that indole-based ligands are promising candidates for future lead optimizations in drug development.
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal.
authors.forename: Josué
authors.initials: J
authors.lastname: Carvalho
authors.affiliation: Univ. Bordeaux, ARNA Laboratory, Inserm U1212, CNRS UMR 5320, IECB, F-33600, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Nottelet
authors.affiliation: Univ. Bordeaux, ARNA Laboratory, Inserm U1212, CNRS UMR 5320, IECB, F-33600, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal.
authors.forename: João A
authors.initials: JA
authors.lastname: Queiroz
authors.affiliation: Univ. Bordeaux, ARNA Laboratory, Inserm U1212, CNRS UMR 5320, IECB, F-33600, France. Electronic address: g.salgado@iecb.u-bordeaux.fr.
authors.forename: Gilmar F
authors.initials: GF
authors.lastname: Salgado
authors.affiliation: CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal. Electronic address: carlacruz@fcsaude.ubi.pt.
authors.forename: Carla
authors.initials: C
authors.lastname: Cruz
mesh_terms: D002942:Circular Dichroism; D054856:G-Quadruplexes; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy
chemical_list: D007211:Indoles; C030374:indole
keywords: Circular dichroism; FRET melting; G-quadruplex; G4 ligands; Indole-based compounds; NMR studies