title: Site-specific control of N7-metal coordination in DNA by a fluorescent purine derivative.
abstract: A synthetic strategy that utilizes O6-protected 8-bromoguanosine gives broad access to C8-guanine derivatives with phenyl, pyridine, thiophene, and furan substituents. The resulting 8-substituted 2'-deoxyguanosines are push-pull fluorophores that can exhibit environmentally sensitive quantum yields (Φ=0.001-0.72) due to excited-state proton-transfer reactions with bulk solvent. Changes in nucleoside fluorescence were used to characterize metal-binding affinity and specificity of 8-substituted 2'-deoxyguanosines. One derivative, 8-(2-pyridyl)-2'-deoxyguanosine (2PyG), exhibits selective binding of Cu(II), Ni(II), Cd(II), and Zn(II) through a bidentate effect provided by the N7 position of guanine and the 2-pyridyl nitrogen atom. Upon incorporation into DNA, 2-pyridine-modified guanine residues selectively bind to Cu(II) and Ni(II) with equilibrium dissociation constants (K(d)) that range from 25 to 850 nM; the affinities depend on the folded state of the oligonucleotide (duplex>G-quadruplex) as well as the identity of the metal ion (Cu>Ni≫Cd). These binding affinities are approximately 10 to 1 000 times higher than for unmodified metal binding sites in DNA, thereby providing site-specific control of metal localization in alternatively folded nucleic acids. Temperature-dependent circular-dichroism studies reveal metal-dependent stabilization of duplexes, but destabilization of G-quadruplex structures upon adding Cu(II) to 2PyG-modified oligonucleotides. These results demonstrate how the addition of a single pyridine group to the C8 position of guanine provides a powerful new tool for studying the effects of N7 metalation on the structure, stability, and electronic properties of nucleic acids.
authors.affiliation: Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Anaëlle
authors.initials: A
authors.lastname: Dumas
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Luedtke
mesh_terms: D001483:Base Sequence; D002104:Cadmium / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry; D054856:G-Quadruplexes; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry; D009841:Oligonucleotides / Q000737:chemistry; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
chemical_list: D005456:Fluorescent Dyes; D008670:Metals; D009841:Oligonucleotides; D011687:Purines; D011725:Pyridines; D002104:Cadmium; D003300:Copper; D009532:Nickel; D004247:DNA; D003849:Deoxyguanosine; D015032:Zinc