Acridine and quindoline oligomers linked through a 4-aminoproline backbone prefer G-quadruplex structures

BackgroundDNA-intercalating drugs are planar molecules with several fused aromatic rings that form stacks between DNA base pairs, reducing the opening and unwinding of the double helix. Recently, interest on intercalating agents has moved in the search for new ligands to G-quadruplex structures.MethodsThe DNA binding properties of 4-aminoproline oligomers functionalized with one, two or three units of acridine and/or quindoline have been analyzed by competitive dialysis. A NMR/molecular dynamics study was performed on G-quadruplex telomeric sequence and the 4-aminoproline dimer carrying two quindolines. A model of the complex with the telomeric DNA quadruplex is described.Results and conclusionsA selectivity of quindoline 4-aminoproline oligomers for G-quadruplex and triplex structures was observed, especially for those quadruplex sequences found in telomeres and in the promoter regions of c-myc and bcl-2 oncogenes. In this model the quindoline dimer is stabilized by π–π stacking interactions between the aromatic rings of the ligand and the nucleobases of the telomeric sequence that are located above and below the molecule.General significanceThe results of this work can be used for the design of new molecules with high affinity to telomeres which may have anticancer properties.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (109 K)Download as PowerPoint slideHighlights► Selectivity of quindoline 4-aminoproline for G-quadruplex and triplex structures. ► NMR/molecular dynamics study on G-quadruplex telomeric and the 4-aminoproline dimer. ► In G-quadruplex model the quindoline dimer is stabilized by π–π stacking.