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Site‐Specific Control of N 7–Metal Coordination in DNA by a Fluorescent Purine Derivative
Author(s) -
Dumas Anaëlle,
Luedtke Nathan W.
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201102349
Subject(s) - chemistry , guanine , stereochemistry , pyridine , metal , oligonucleotide , circular dichroism , fluorescence , nucleobase , benzimidazole , dna , crystallography , medicinal chemistry , nucleotide , organic chemistry , biochemistry , physics , quantum mechanics , gene
A synthetic strategy that utilizes O 6‐protected 8‐bromoguanosine gives broad access to C 8‐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 N 7 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 n M ; 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 C 8 position of guanine provides a powerful new tool for studying the effects of N 7 metalation on the structure, stability, and electronic properties of nucleic acids.