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.

Fluorescent Probes for G‐Quadruplex Structures

“…Fluorescent guanosine derivatives with tunable photophysical properties can be generated by adding a vinyl, styryl, aryl, or heteroaryl group to the 8-position of 2'-deoxyguanosine. [221] The resulting derivatives (e.g., 39-42; Scheme 12) are compatible with G-quadruplex and duplex DNA folding, and cause little or no thermodynamic or structural perturbation (DDG % À1.5 to +1 kcal mol À1 ), compared to unmodified guanine residues. [70,97,98,[221][222][223] The fluorescence properties of 8-substitued guanosines are highly sensitive to their local environment, and can reflect the folded state of the oligonucleotides containing them.…”

Synthesis of 5‐/8‐Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolec­ular Chemistry

“…[8], [12], [24] The low oxidation potential of this base or its ability to coordinate organometallic catalytic species are cited among the causes that would explain such lack of reactivity. [12] Conversion to different functionalized derivatives like 6-alkoxy-, [8], [24], [25] or 6-halogenopurines, which, at the same time, may exhibit a higher selectivity in the alkylation reaction, is an alternative. Unfortunately, the use of these starting reagents involve higher costs and an increase in the number of reaction steps, which results in poorer overall yields.…”

Excited-State Proton Transfer and Phototautomerism in Nucleobase and Nucleoside Analogs: A Mini-Review

“…[84,85] It should be also recalled that nucleoside analogs capable of intramolecular ESPT were developed and applied to the modified DNA studies. [31,[86][87][88] Recently, Dumas and Luedtke [89] reported the ESPT to occur in a series of highly fluorescent C8-substituted pyridyl-guanosine derivatives, but the described solvent effects are not as radical as in 8-azapurine derivatives, and Stokes' shifts are <10,000 cm −1 , so these systems, although obviously useful as fluorescence probes, must be further elaborated. The postulated ESPT in 2-aminopurine [90] needs reconsideration for reasons similar as above.…”