Design, synthesis and evaluation of 4,7-diamino-1,10-phenanthroline G-quadruplex ligands.
A series of 4,7-diamino-1,10-phenanthroline derivatives carrying positively charged side chains has been synthesized, and their G-quadruplex interaction evaluated by circular dichroism (CD) and surface plasmon resonance (SPR). In absence of side chains, 4,7-diamino-1,10-phenanthroline exhibits a weak but significant G-quadruplex stabilizing effect, compared to no stabilization by 1,10-phenanthroline. We hypothesize that this effect is due to increased basicity of the phenanthroline nitrogens and protonation or ion chelation to form a central positive charge which stack on the G-tetrad above the central ionic column. Introduction of positively charged side chains results in compounds with appreciable G-quadruplex stabilizing properties and high aqueous solubility, with the longer side chains giving more potent compounds. Ligands carrying guanidine side chains in general show higher quadruplex stabilizing activity and distinctly slower kinetic properties than their amino and dimethylamino analogues, possibly due to specific hydrogen bond interactions with the G-quadruplex loops.
Nielsen
Mads Corvinius
MC
Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Borch
Jonas
J
Ulven
Trond
T
D001665:Binding Sites; D002942:Circular Dichroism / Q000379:methods; D015195:Drug Design; D054856:G-Quadruplexes / Q000528:radiation effects; D006860:Hydrogen Bonding; D008024:Ligands; D008745:Methylation; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D010618:Phenanthrolines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance / Q000379:methods; D016615:Telomere / Q000737:chemistry
D008024:Ligands; D010618:Phenanthrolines; C025205:1,10-phenanthroline