Direct determination of tautomerism in purine derivatives by low-temperature NMR spectroscopy

Sečkářová, Pavlı́na; Marek, Radek; Maliňáková, Kateřina; Kolehmainen, Erkki; Hocková, Dana; Hocek, Michal; Sklenář, Vladimı́r

doi:10.1016/j.tetlet.2004.06.088

Cited by 49 publications

(17 citation statements)

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“…[18,19] The differences in electron distribution between the N7-H and N9-H forms of purine derivatives as reflected in the isotropic 13 C and 15 N chemical shifts are well known. [3,20] It has also been demonstrated that the differences in the isotropic chemical shifts between the two tautomers are very similar to the differences observed for the corresponding N7/N9 substituted compounds, [3] which enables us to use here the N-substituted adenines as model compounds for adenine tautomers. The CST data [21,22] as well as the NICS indices [23,24] have already been reported for the major N9-H tautomer of adenine.…”

Section: Introductionmentioning

confidence: 65%

“…[20,26] This is true not only for protonated but also for substituted nitrogen atoms, which enables us to use various N-substituted purines as model compounds for purine tautomers. [3,27,28] The isotropic chemical shift of a substituted (or protonated) nitrogen atom of the purine ring is significantly smaller than the isotropic chemical shifts of nonsubstituted ones. Another typical marker of the N7/N9 substitution (protonation) is the chemical shift of nitrogen N3, which is always smaller in the case of N9-substituted compounds.…”

Section: 4mentioning

confidence: 99%

“…Substitution of the purine ring influences the tautomeric equilibrium, and for some compounds the N7-H form prevails. [3,4] However, significant populations of the N1-H and N3-H tautomers have not been experimentally observed.…”

Section: Introductionmentioning

confidence: 99%

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Chemical Shift Tensors in Isomers of Adenine: Relation to Aromaticity of Purine Rings?

et al. 2010

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The (13)C and (15)N chemical shift tensors are measured, calculated, and compared for three N-benzyladenine isomers with an attempt to characterize differences in electron distribution in the purine ring related to the position of the substituent. Furthermore, the aromaticity of the purine rings is evaluated on the basis of nucleus-independent chemical shifts, and variations among the isomers are discussed. Both parameters indicate significant differences between the electronic properties of the N3-substituted compound and the N7/N9 pair of structures, which can be viewed more generally as the reason for the different stabilities of the individual tautomers.

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Section: Introductionmentioning

confidence: 65%

Section: 4mentioning

confidence: 99%

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Chemical Shift Tensors in Isomers of Adenine: Relation to Aromaticity of Purine Rings?

et al. 2010

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“…Furthermore, adenine can exist in different tautomeric forms with the most stable one being the 9H-amino tautomer ( Figure 1). [13][14][15] Protonation of the 9H-tautomer usually takes place at the N1 nitrogen. 11,[16][17][18][19][20] By contrast, while N 6 -benzyladenine 21 and kinetin 22 crystallize in the expected 9H-tautomeric form, the N3-protonated 7H-tautomer ( Figure 1) was observed in the crystal structures of their bromide, chloride and dihydrogenphosphate salts.…”

Section: Introductionmentioning

confidence: 99%

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine

McHugh

Erxleben

2011

Crystal Growth & Design

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Co-crystal and salt formation of the kinetin analogue N 6 -benzyladenine with the pharmaceutically acceptable co-crystal and salt formers maleic acid, oxalic acid, glutaric acid, succinic acid, benzoic acid and fumaric acid has been studied by solid-state and solvent-drop grinding in combination with X-ray powder diffraction. In all cases salt or co-crystal formation was observed. Single crystals of (bzadeH + )(mal -) (1) and (bzadeH + )2(ox 2-) (2) were obtained by solution crystallization and the X-ray structures are reported along with that of (adeH + )2(mal -)2 . ade . 2H2O (3) (bzadeH + = N 6 -benzyladeninium, adeH + = adeninium, ade = adenine, mal -= hydrogen maleate, ox 2-= oxalate). The hydrogen-bonding motifs in 1 -3 are discussed. The salts contain a robust bzadeH + -carboxylate or ade-carboxylate R2 2 (9) heterosynthon involving the protonated Hoogsteen sites (N6-H, N7-H) of bzadeH + and ade. Molecular recognition between the protonated Hoogsteen site and the carboxylate group stabilizes the unusual 7H,9H tautomer of bzadeH + in 2 and the non-canonical 7H-adenine tautomer in 3.* To whom correspondence should be addressed. ABSTRACT Co-crystal and salt formation of the kinetin analogue N 6 -benzyladenine with the pharmaceutically acceptable co-crystal and salt formers maleic acid, oxalic acid, glutaric acid, succinic acid, benzoic acid and fumaric acid has been studied by solid-state and solvent-drop grinding in combination with X-ray powder diffraction. In all cases salt or co-crystal formation was observed. Single crystals of (bzadeH + )(mal -) (1) and (bzadeH + )2(ox 2-) (2) were obtained by solution crystallization and the X-ray structures are reported along with that of (adeH + )2(mal -)2 . ade . 2H2O (3) (bzadeH + = N 6 -benzyladeninium, adeH + = adeninium, ade = adenine, mal -= hydrogen maleate, ox 2-= oxalate). The hydrogen-bonding motifs in 1 -3 are discussed. The salts contain a robust bzadeH + -carboxylate or ade-carboxylate R2 2 (9) heterosynthon involving the protonated Hoogsteen sites (N6-H, N7-H) of bzadeH + and ade. Molecular recognition between the protonated Hoogsteen site and the carboxylate group stabilizes the unusual 7H,9H tautomer of bzadeH + in 2 and the non-canonical 7H-adenine tautomer in 3.3

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“…In a search for a chemical rationale to explain the ambiguous pairing of KP1212 during replication, the present study revealed that the compound readily adopts multiple tautomeric forms, some of which were unexpected. Previously, spectroscopic methods (e.g., UV, Raman, NMR) have been used to study tautomerism of nucleobases (37,39,40). In the current work, we also used a battery of spectroscopic tools (1D, 2D, and variable temperature NMR; FTIR; and 2D IR) (41) to quantify and structurally characterize the array of tautomers exhibited by KP1212.…”

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confidence: 99%

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

Fedeles

Singh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Unlike conventional antiviral therapy, lethal mutagenesis is a therapeutic strategy that exploits the high mutation rates of certain viruses. It works by intentionally increasing the viral mutation rate, causing excessive error accumulation and viral population collapse. The mutagenic nucleoside analog 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212) is specifically designed to use lethal mutagenesis against HIV. The mechanism of KP1212 mutagenesis was proposed to involve tautomerism—the repositioning of active protons on the nucleic acid base on a fast time scale. Using a multifaceted approach, we demonstrate that KP1212 exists in multiple tautomeric forms, and that the tautomeric distribution correlates with the mutagenic properties of KP1212. This work also provides a toolset for studying tautomerism in nucleic acids and developing the next-generation antiviral lethal mutagens.

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Direct determination of tautomerism in purine derivatives by low-temperature NMR spectroscopy

Cited by 49 publications

References 29 publications

Chemical Shift Tensors in Isomers of Adenine: Relation to Aromaticity of Purine Rings?

Chemical Shift Tensors in Isomers of Adenine: Relation to Aromaticity of Purine Rings?

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

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Direct determination of tautomerism in purine derivatives by low-temperature NMR spectroscopy

Cited by 49 publications

References 29 publications

Chemical Shift Tensors in Isomers of Adenine: Relation to Aromaticity of Purine Rings?

Chemical Shift Tensors in Isomers of Adenine: Relation to Aromaticity of Purine Rings?

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N6-Substituted Adenine

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

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Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine