Systematic Tables of Mono- and Poly-N-methylated Adenines: Acid Dissociation Constants and UV and NMR Spectral Data

Fujii, Tozo; Itaya, Taisuke

doi:10.3987/rev-99-523

Cited by 14 publications

(18 citation statements)

References 48 publications

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“…However, unlike singly substituted N 6 -dA derivatives, which exhibit one- proton signal at ~ 8 ppm corresponding to the exocyclic amino group, spectra of compounds 2a-base , 2b-base , and 2c-base lacked the N 6 -H proton signal, consistent with bis -alkylation of the N 6 position of adenine. 13 C chemical shifts of the aromatic part of the molecule were similar to those reported for other N 6 -alkyladenines (45,51). NMR spectra of compounds 2a-base and 2b-base were identical, consistent with their enantiomeric relationship.…”

Section: Resultssupporting

confidence: 82%

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Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Seneviratne

Antsypovich

Goggin

et al. 2009

Chem. Res. Toxicol.

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Abstract1,2,3,4-Diepoxybutane (DEB)1 is considered the ultimate carcinogenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant present in urban air. Although it preferentially modifies guanine within DNA, DEB induces a large number of A → T transversions, suggesting that it forms strongly mispairing lesions at adenine nucleobases. We now report the discovery of three potentially mispairing exocyclic adenine lesions of DEB:. The structures and stereochemistry of the novel DEB-dA adducts were determined by a combination of UV and NMR spectroscopy, tandem mass spectrometry, and independent synthesis. We found that synthetic N 6 -(2-hydroxy-3,4-epoxybut-1-yl)-2′-deoxyadenosine (compound 1) representing the product of N 6 -adenine alkylation by DEB spontaneously cyclizes to form 3 under aqueous conditions or 2 under anhydrous conditions in the presence of organic base. Compound 3 can be interconverted with 4 by a reversible unimolecular pericyclic reaction favoring 4 as a more thermodynamically stable product. Both 3 and 4 are present in double stranded DNA treated with DEB in vitro and in liver DNA of laboratory mice exposed to 1,3-butadiene by inhalation. We propose that in DNA under physiological conditions, DEB alkylates the N-1 position of adenine in DNA to form N1- (2-hydroxy-3,4-epoxybut-1-yl)adenine adducts, which undergo an S N 2-type intramolecular nucleophilic substitution and rearrangement to give 3 (minor) and 4 (major). Formation of exocyclic DEB-adenine lesions following exposure to 1,3-butadiene provides a possible mechanism of mutagenesis at the A:T base pairs.

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Section: Resultssupporting

confidence: 82%

“…Other N1-alkyladenines are known to be positively charged in aqueous solutions at a neutral pH (the pK a of 1-methyladenine is 8.25)(45), with the charge localized mainly at the N1 position. HPLC behavior of compounds 3 and 4 , e.g.…”

Section: Resultsmentioning

confidence: 99%

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Seneviratne

Antsypovich

Goggin

et al. 2009

Chem. Res. Toxicol.

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“…7B, which is published as supporting information on the PNAS web site), similar to those reported for N9-methyl-Ade and its isomers, N1-methyl-Ade and N3-methyl-Ade, respectively (23). The pH is known to differently affect the absorbance spectrum of the various methyl-adenine isomers: whereas the max value of N1-methyl adenine changes considerably over a pH range from 5 to 11, max values of N9-and N3-methyl-adenine remain unchanged (23). Thus, we compared the effect of pH on max of P8, P11, and AMP*.…”

Section: Resultssupporting

confidence: 65%

ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells

Basile

Taglialatela‐Scafati²,

Damonte³

et al. 2005

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

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ADP-ribosyl cyclases are ubiquitous enzymes responsible for synthesis from NAD ؉ of the intracellular calcium-releasing signal molecules cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP ؉ ). Here, we show that cyclases from lower and higher Metazoa also synthesize three adenylic dinucleotides from cADPR and adenine: diadenosine diphosphate and two isomers thereof. These dinucleotides are present and metabolized in mammalian cells and affect intracellular calcium and cell proliferation. The diadenosine diphosphate isomers are naturally occurring nucleotides containing an N-glycosidic bond different from the usual C1 -N9. The identification of these members of the family of NAD ؉ -derived, calcium-active nucleotides opens new areas of investigation into their functional cooperation with cADPR and NAADP ؉ and into their involvement in the physiology and pathology of calcium-controlled cell functions.adenylic dinucleotides ͉ NAD ϩ ͉ cyclic ADP-ribose ͉ cytotoxicity

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“…Importantly, the corresponding correlation that would be expected for N7 ade attachment was not observed (H5′′ a,b to C5 ade ). Finally, the UV spectra of 3 a and 4 a both have absorbance maxima at 262 nm, rather than at 270 nm, as would be characteristic of an N7‐substituted adenine 25…”

Section: Resultsmentioning

confidence: 98%

“…Once each proton spectrum had been assigned, the carbon spectrum was assigned by using 1 H, 13 C gHSQC. Finally, a wealth of literature precedent24, 25 and 1 H, 13 C gHSQC facilitated the assignment of each of the proton resonances of the pyrimidine or purine rings.…”

Section: Resultsmentioning

confidence: 99%

A Tale of Two Targets: Differential RNA Selectivity of Nucleobase–Aminoglycoside Conjugates

Blount

Tor

2006

ChemBioChem

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Aminoglycoside antibiotics are RNA-binding polyamines that can bind with similar affinities to structurally diverse RNA targets. To design new semisynthetic aminoglycosides with improved target selectivity, it is important to understand the energetic and structural basis by which diverse RNA targets recognize similar ligands. It is also imperative to discover how novel aminoglycosides could be rationally designed to have enhanced selectivity for a given target. Two RNA drug targets, the prokaryotic ribosomal A-site and the HIV-1 TAR, provide an excellent model system in which to dissect the issue of target selectivity, in that they each have distinctive interactions with aminoglycosides. We report herein the design, synthesis, and binding activity of novel nucleobase-aminoglycoside conjugates that were engineered to be more selective for the A-site binding pocket. Contrary to the structural design, the conjugates bind the A-site more weakly than does the parent compound and bind the TAR more tightly than the parent compound. This result implies that the two RNA targets differ in their ability to adapt to structurally diverse ligands and thus have inherently different selectivities. This work emphasizes the importance of considering the inherent selectivity traits of the RNA target when engineering new ligands.

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Systematic Tables of Mono- and Poly-N-methylated Adenines: Acid Dissociation Constants and UV and NMR Spectral Data

Cited by 14 publications

References 48 publications

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

Exocyclic Deoxyadenosine Adducts of 1,2,3,4-Diepoxybutane: Synthesis, Structural Elucidation, and Mechanistic Studies

ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells

A Tale of Two Targets: Differential RNA Selectivity of Nucleobase–Aminoglycoside Conjugates

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