Selective recognition of pyrimidine-pyrimidine DNA mismatches by distance-constrained macrocyclic bis-intercalators.
Binding of three macrocyclic bis-intercalators, derivatives of acridine and naphthalene, and two acyclic model compounds to mismatch-containing and matched duplex oligodeoxynucleotides was analyzed by thermal denaturation experiments, electrospray ionization mass spectrometry studies (ESI-MS) and fluorescent intercalator displacement (FID) titrations. The macrocyclic bis-intercalators bind to duplexes containing mismatched thymine bases with high selectivity over the fully matched ones, whereas the acyclic model compounds are much less selective and strongly bind to the matched DNA. Moreover, the results from thermal denaturation experiments are in very good agreement with the binding affinities obtained by ESI-MS and FID measurements. The FID results also demonstrate that the macrocyclic naphthalene derivative BisNP preferentially binds to pyrimidine-pyrimidine mismatches compared to all other possible base mismatches. This ligand also efficiently competes with a DNA enzyme (M.TaqI) for binding to a duplex with a TT-mismatch, as shown by competitive fluorescence titrations. Altogether, our results demonstrate that macrocyclic distance-constrained bis-intercalators are efficient and selective mismatch-binding ligands that can interfere with mismatch-binding enzymes.
Bahr
Matthias
M
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany.
Gabelica
Valérie
V
Granzhan
Anton
A
Teulade-Fichou
Marie-Paule
MP
Weinhold
Elmar
E
D000166:Acridines / Q000737:chemistry*; D020137:Base Pair Mismatch; D001667:Binding, Competitive; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D007364:Intercalating Agents / Q000737:chemistry*; D008024:Ligands; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D009691:Nucleic Acid Denaturation; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization; D013696:Temperature; D013941:Thymine / Q000737:chemistry
D000166:Acridines; C451420:BisA compound; D001952:Bridged-Ring Compounds; D007364:Intercalating Agents; D008024:Ligands; D009281:Naphthalenes; D004247:DNA; C059680:DNA modification methylase TaqI; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific); D013941:Thymine