Metal-Ion-Mediated Base Pairing between Natural Nucleobases and Bidentate 3,5-Dimethylpyrazolyl-Substituted Purine Ligands

Abstract

The potential of three modified purine bases, namely, 6-(3,5-dimethylpyrazol-1-yl)purine, 2-(3,5-dimethylpyrazol-1-yl)hypoxanthine, and 2-(3,5-dimethylpyrazol-1-yl)adenine, for metal-ion-mediated base pairing within an oligonucleotide environment has been investigated. The respective modified nucleosides were incorporated in the middle of 9-mer 2'-O-methyl oligonucleotides and the hybridization of these modified oligonucleotides with their unmodified counterparts studied by UV and CD spectrometry in the absence and presence of Cu(2+) or Zn(2+). All of the modified oligonucleotides formed more stable duplexes in the presence of divalent metal ions than in the absence thereof, but with different preferences for the complementary oligonucleotide. The oligonucleotide incorporating 2-(3,5-dimethylpyrazol-1-yl)hypoxanthine readily accepted any of the natural nucleobases opposite to this modified base regardless of whether Cu(2+) or Zn(2+) was used as the bridging metal ion. The other two oligonucleotides, on the other hand, were much more discriminating, exhibiting markedly elevated Tm values only in the presence of Cu(2+) and only when certain natural nucleobases were paired with the modified one. The origin of the selectivity (or promiscuity) of the metal-ion-mediated base pairing is discussed in terms of the ability of the modified nucleobases, as well as their natural counterparts, to serve as anionic ligands.

Metal complexes of 6-pyrazolylpurine derivatives as models for metal-mediated base pairs

“…By determining the molecular structures of Cu 2+ complexes of the model nucleobase 9-methyl-6-(3,5-dimethylpyrazol-1-yl)purine, the coordination pattern previously proposed for a Cu 2+ -mediated hetero base pair involving such artificial nucleoside [32] could be unambiguously confirmed. Moreover, molecular structures of metal complexes of the sterically less crowded purine derivative 9-methyl-6-pyrazol-1-ylpurine indicate that the corresponding nucleoside should be capable of forming metal-mediated homo base pairs.…”

“…Chemical structures of 3,5-dimethylpyrazolyl-substituted derivatives of purine, adenine, and hypoxanthine (R = nucleic acid backbone) as previously reported by Lönnberg et al[32,33,35].…”

“…This ambident behavior of 6-substituted purine derivatives has recently been demonstrated using 6-furylpurine [18,19]. As no molecular structures had been available for metal complexes of 6-(3,5-dimethylpyrazol-1-yl)purine, Cu 2+ -binding to the N7 position of this purine derivative had been suggested based on a comparison with the complexation behavior of the closely related adenine moiety [32]. We report here a systematic structural study of the metalbinding behavior of 9-methyl-6-(3,5-dimethylpyrazol-1-yl)purine 2, acting as a model nucleobase.…”

“…Most recently, Lönnberg et al have introduced a family of artificial purine-derived nucleosides that were designed with the aim of discriminating a natural nucleobase located opposite the artificial nucleoside [32][33][34][35]. Oligonucleotides capable of specifically recognizing short nucleic acid sequences are relevant in RNA interference and other therapeutic applications for the treatment of genetic disorders [36,37].…”

Concomitant Site‐Specific Incorporation of Silver(I) and Mercury(II) Ions into a DNA Duplex

“…[7] Most recently,t he first Cu Imediated base pair stable in aqueouss olutionw as reported. [8] Based on such metal-containing nucleic acids, several promising applications have been proposeda nd investigated, including charge transfer throughD NA, [9] DNA-templated metal nanoparticle generation, [10] DNA-based hybrid catalysis, [11] metal-ion sensors, [12] recognition of oligonucleotide sequences, [13] metal-responsive materials, [6a, 7b, 14] and expansion of the geneticf our letter code, [4i] to name just af ew.…”