Macrocyclic DNA-mismatch-binding ligands: structural determinants of selectivity.
A collection of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was prepared by one- or two-step condensation of aromatic dialdehydes with aliphatic diamines; notably, the heterodimeric scaffolds were synthesized for the first time. The binding of these macrocycles to DNA duplexes containing a mispaired thymine residue (TX), as well as to the fully paired control (TA), was investigated by thermal denaturation and fluorescent-intercalator-displacement experiments. The bisnaphthalene derivatives, in particular, the 2,7-disubstituted ones, have the highest selectivity for the TX mismatches, as these macrocycles show no apparent binding to the fully paired DNA. By contrast, other macrocyclic ligands, as well as seven conventional DNA binders, show lesser or no selectivity for the mismatch sites. The study demonstrates that the topology of the ligands plays a crucial role in determining the mismatch-binding affinity and selectivity of the macrocyclic bisintercalators.
Granzhan
Anton
A
UMR176 CNRS, Institut Curie, Centre de Recherche, Centre Universitaire, 91405 Orsay, France.
Largy
Eric
E
Saettel
Nicolas
N
Teulade-Fichou
Marie-Paule
MP
D000447:Aldehydes / Q000737:chemistry; D020137:Base Pair Mismatch; D004247:DNA / Q000737:chemistry*; D003959:Diamines / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D009281:Naphthalenes / Q000737:chemistry; D044366:Transition Temperature
D000447:Aldehydes; D003959:Diamines; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D008024:Ligands; D047028:Macrocyclic Compounds; D009281:Naphthalenes; C031721:naphthalene; D004247:DNA