Modeling and biological investigations of an unusual behavior of novel synthesized acridine-based polyamine ligands in the binding of double helix and G-quadruplex DNA.
Three novel 2,7-substituted acridine derivatives were designed and synthesized to investigate the effect of this functionalization on their interaction with double-stranded and G-quadruplex DNA. Detailed investigations of their ability to bind both forms of DNA were carried out by using spectrophotometric, electrophoretic, and computational approaches. The ligands in this study are characterized by an open-chain (L1) or a macrocyclic (L2, L3) framework. The aliphatic amine groups in the macrocycles are joined by ethylene (L2) or propylene chains (L3). L1 behaved similarly to the lead compound m-AMSA, efficiently intercalating into dsDNA, but stabilizing G-quadruplex structures poorly, probably due to the modest stabilization effect exerted by its protonated polyamine chains. L2 and L3, containing small polyamine macrocyclic frameworks, are known to adopt a rather bent and rigid conformation; thus they are generally expected to be sterically impeded from recognizing dsDNA according to an intercalative binding mode. This was confirmed to be true for L3. Nevertheless, we show that L2 can give rise to efficient π-π and H-bonding interactions with dsDNA. Additionally, stacking interactions allowed L2 to stabilize the G-quadruplex structure: using the human telomeric sequence, we observed the preferential induction of tetrameric G-quadruplex forms. Thus, the presence of short ethylene spacers seems to be essential for obtaining a correct match between the binding sites of L2 and the nucleobases on both DNA forms investigated. Furthermore, current modeling methodologies, including docking and MD simulations and free energy calculations, provide structural evidence of an interaction mode for L2 that is different from that of L3; this could explain the unusual stabilizing ability of the ligands (L2>L3>L1) toward G-quadruplex that was observed in this study.
Bazzicalupi
Carla
C
Department of Chemistry "Ugo Schiff", University of Florence, Italy. carla.bazzicalupi@unifi.it
Chioccioli
Matteo
M
Sissi
Claudia
C
Porcù
Elena
E
Bonaccini
Claudia
C
Pivetta
Claudia
C
Bencini
Andrea
A
Giorgi
Claudia
C
Valtancoli
Barbara
B
Melani
Fabrizio
F
Gratteri
Paola
P
D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011073:Polyamines / Q000737:chemistry*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D044366:Transition Temperature
D000166:Acridines; D008024:Ligands; D011073:Polyamines; D004247:DNA; D019098:Telomerase