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Site-specific control of N7-metal coordination in DNA using a fluorescent purine derivative


Dumas, A; Luedtke, N W (2012). Site-specific control of N7-metal coordination in DNA using a fluorescent purine derivative. Chemistry - A European Journal, 18(1):245-254.

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 CuII, NiII, CdII, and ZnII 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 CuII and NiII with equilibrium dissociation constants (Kd) 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 CuII 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.

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 CuII, NiII, CdII, and ZnII 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 CuII and NiII with equilibrium dissociation constants (Kd) 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 CuII 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Date:1 January 2012
Deposited On:05 Mar 2012 10:08
Last Modified:22 Sep 2018 07:30
Publisher:Wiley-Blackwell
ISSN:0947-6539
Funders:University of Zürich Forschungskredit 57131901, Swiss National Science Foundation 130074
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/chem.201102349
PubMed ID:22143992
Project Information:
  • : Funder
  • : Grant ID
  • : Project TitleUniversity of Zürich Forschungskredit 57131901
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation 130074

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