title: Recognition of G-quadruplex DNA by triangular star-shaped compounds: with or without side chains?
abstract: We report the synthesis of two new series of triangular aromatic platforms, either with three aminoalkyl side chains (triazatrinaphthylene series, TrisK: six compounds), or without side chains (triazoniatrinaphthylene, TrisQ). The quadruplex-DNA binding behavior of the two series, which differ essentially by the localization of the cationic charges, was evaluated by means of FRET-melting and G4-FID assays. For the trisubstituted triazatrinaphthylenes (TrisK), the length of the substituents and the presence of terminal hydrogen-bond-donor groups (NH(2)) were shown to be crucial for ensuring a high quadruplex affinity (ΔT(1/2) values of up to 20 °C at 1 μM for the best candidate, TrisK3-NH) and selectivity versus duplex DNA. Subsequently, comparison of data collected on both the telomeric- and c-myc-quadruplex showed that the nonsubstituted TrisQ is even more efficient than TrisK3-NH, both in terms of quadruplex affinity (ΔT(1/2)=26 °C in K(+) buffer) and selectivity versus duplex DNA. Structural considerations conducted with the c-myc quadruplex indicate that both TrisK3-NH and TrisQ stack well onto the G-quartet but in an offset position, which might be influenced by the formation of multiple hydrogen bonds with the target in the former case. Finally, the nonsubstituted TrisQ displays a binding profile very similar to some of the best quadruplex binders, BRACO-19 and bisquinolinium 360A, used herein as references, and thereby represents a highly promising novel molecular design for quadruplex recognition.
authors.affiliation: Institut Curie, Centre de Recherche, CNRS UMR176, Centre Universitaire Paris XI, Bât. 110, 91405 Orsay, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Bertrand
authors.forename: Anton
authors.initials: A
authors.lastname: Granzhan
authors.forename: David
authors.initials: D
authors.lastname: Monchaud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Saettel
authors.forename: Régis
authors.initials: R
authors.lastname: Guillot
authors.forename: Sarah
authors.initials: S
authors.lastname: Clifford
authors.forename: Aurore
authors.initials: A
authors.lastname: Guédin
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mergny
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Teulade-Fichou
mesh_terms: D000166:Acridines / Q000737:chemistry; D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry; D054856:G-Quadruplexes; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D001391:Azo Compounds; D006571:Heterocyclic Compounds; D008024:Ligands; C454064:BRACO-19