Metal ion-binding properties of 9-(4-phosphonobutyl)adenine (dPMEA), a sister compound of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), and quantification of the equilibria involving four Cu(PMEA) isomers

Gómez‐Coca, Raquel B.; Kapinos, Larisa E.; Holý, Antonı́n; Vilaplana, Rosario A.; González-Vı́lchez, Francisco; Sigel, Helmut

doi:10.1039/b001588l

Cited by 36 publications

(55 citation statements)

References 43 publications

(53 reference statements)

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“…In fact, this means that in 1 ml of a 10 -3 M Ado solution from the 6 × 10 17 adenosine molecules present, about 2.4 × 10 16 molecules carry the proton at N7. However, the relatively high basicity of N7, which is reflected in the mentioned ratios, is of relevance for metal ion binding at this site [33][34][35], but it is not of relevance for the formation of tautomeric species in the physiological pH range of about 7.5 since under these conditions the proton is already lost, its pK a value being about 4 (Table 3, entry 4).…”

Section: Formation Degrees Of Some Rare Tautomers Of Nucleobase Residuesmentioning

confidence: 99%

Acid-base properties of purine residues and the effect of metal ions: Quantification of rare nucleobase tautomers

Sigel

2004

Pure and Applied Chemistry

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Abstract:The macro acidity constants valid for aqueous solutions of several adenine, guanine, and hypoxanthine derivatives are summarized. It is shown how the application of the corresponding constants, e.g., for 7,9-dimethyladenine, allows a quantification of the intrinsic acidic properties of the (N1)H 0/+ and (N7)H + sites via micro acidity constants, and how to use this information for the calculation of the tautomeric ratios regarding the monoprotonated species, that is, N7-N1ؒH versus HؒN7-N1, meaning that in one isomer H + is at the N1 site and in the other at N7. It is further shown that different metal ions coordinated to a given site, e.g., N7, lead to a different extent of acidification, e.g., at (N1)H; the effect decreases in the series Cu 2+ > Ni 2+ > Pt 2+~ Pd 2+ . Moreover, the application of micro acidity constants proves that the acidifications are reciprocal and identical. This means, Pt 2+ coordinated to (N1) -/0 sites in guanine, hypoxanthine, or adenine residues acidifies the (N7)H + unit to the same extent as (N7)-coordinated Pt 2+ acidifies the (N1)H 0/+ site. In other words, an apparently increased basicity of N7 upon Pt 2+ coordination at (N1) -/0 sites disappears if the micro acidity constants of the appropriate isocharged tautomers of the ligand are properly taken into account. There is also evidence that proton-proton interactions are more pronounced than divalent metal ion-proton interactions, and that these in turn are possibly larger than divalent metal ion-metal ion interactions. The indicated quantifications of the acid-base properties are meaningful for nucleic acids including the formation of certain nucleobase tautomers in low concentrations, which could give rise to mutations.

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Section: Formation Degrees Of Some Rare Tautomers Of Nucleobase Residuesmentioning

confidence: 99%

Acid-base properties of purine residues and the effect of metal ions: Quantification of rare nucleobase tautomers

Sigel

2004

Pure and Applied Chemistry

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“…Since it has been shown previously [41,46] that in the Cu(PMEA) species not only equilibrium 1 with the ether oxygen interaction operates but that also the adenine residue is involved, mainly via N3 and to a small extent also via N7 [46], we have summarized the log D M/PMEA values in column 5 of Table 4 and the differences according to Eq. 12 in column 8 at the Table 3 Stability constant comparisons for the M(PA) complexes, where PA 2À =8,8aPMEA 2À or 9,8aPMEA 2À , according to Eq.…”

Section: (Oh)mentioning

confidence: 99%

“…To complete the picture, the results regarding the previously established [41,46] equilibrium scheme 16 need to be summarized shortly. The two isomeric species M(PA) op and M(PA) cl/O have been discussed and defined above; they correspond to equilibrium 1.…”

Section: Cu(98apmea) and Related Systems A Four Isomer Problemmentioning

confidence: 99%

“…The most thoroughly studied system of this kind is Cu(PMEA) [46]: the formation degrees for any Cu(PMEA) complex concentrations are 17±3%, 34±10%, 41±12% and 7.7±5.3% (errors 3r) for Cu(PMEA) op , Cu(PMEA) cl/O , Cu(PMEA) cl/O/N3 and Cu(PMEA) cl/N7 , respectively, showing that the macrochelated isomer involving N7 is a minority species; the important isomers involve the ether oxygen either in the form of Cu(PMEA) cl/O or together with N3 as Cu(PMEA) cl/O/N3 . Interestingly, the isomeric distribution for the Cu(9,8aPMEA) system is within the error limits (3r) identical with that for the mentioned Cu(PMEA) system; the values for Cu(9,8PMEA) op , Cu(9,8aPMEA) cl/O , Cu(9,8aPMEA) cl/O/N3 and Cu(9,8aPMEA) cl/N7 are 15±3%, 30±10%, 48±11% and 6.8±4.7%, respectively [41].…”

Section: Cu(98apmea) and Related Systems A Four Isomer Problemmentioning

confidence: 99%

“…The stability constants determined are concentration constants. All equilibrium constants were calculated by curvefitting procedures in the way and with the equipment described previously [45,46].…”

Section: Potentiometric Ph Titrationsmentioning

confidence: 99%

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Quantification of isomeric equilibria formed by metal ion complexes of 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine (8,8aPMEA) and 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA). Derivatives of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

et al. 2004

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Formation of Ternary Complexes by Coordination of (Diethylenetriamine)Platinum(II) to N1 or N7 of the Adenine Moiety of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA): Comparison of the Acid-Base and Metal-Ion-Binding Properties of PMEA, (Dien)Pt(PMEA-N1), and (Dien)Pt(PMEA-N7)

et al. 2001

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The synthesis of (Dien)Pt(PMEA-N1), where Dien = diethylenetriamine and PMEA2- = dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is described. The acidity constants of the threefold protonated H3[(Dien)Pt(PMEA-N1)]3+ complex were determined and in part estimated (UV spectrophotometry and potentiometric pH titration): The release of the proton from the (N7)H+ site in H4[(Dien)Pt(PMEA-N1)]3+ occurs with a rather low pKa (= 0.52+/-0.10). The release of the proton from the -P(O)2(OH) group (pKa = 6.69+/-0.03) in H[(Dien)Pt(PMEA-N1)]+ is only slightly affected by the N1-coordinated (Dien)Pt2+ unit. Comparison with the acidic properties of the H[(Dien)Pt(PMEA-N7)]+ species provides evidence that in the (Dien)Pt(PMEA-N7) complex in aqueous solution an intramolecular, outer-sphere macrochelate is formed through hydrogen bonds between the -PO3(2-) residue of PMEA2- and a PtII-coordinated (Dien)NH2 group; its formation degree amounts to about 40%. The stability constants of the M[(Dien)Pt(PMEA-N1)]2+ complexes with M2+ = Mg2+, Ca2+, Ni2+, Cu2+ and Zn2+ were measured by potentiometric pH titrations in aqueous solution at 25 degrees C and I = 0.1 M (NaNO3). Application of previously determined straight-line plots of log K(M(R-PO3))M versus pK(H(R-PO3)H for simple phosph(on)ate ligands. R-PO3(2-), where R represents a non-inhibiting residue without an affinity for metal ions, proves that the primary binding site of (Dien)Pt(PMEA-N1) is the phosphonate group with all metal ions studied; in fact, Mg2+, Ca2+ and Ni2+ coordinate (within the error limits) only to this site. For the Cu[(Dien)Pt(PMEA-N1)]2+ and Zn[(Dien)Pt(PMEA-N1)]2- systems also the formation of five-membered chelates involving the ether oxygen of the -CH2-O-CH2-PO3(2-) residue could be detected; the formation degrees are about 60% and 30%, respectively. The metal-ion-binding properties of the isomeric (Dien)Pt(PMEA-N7) species studied previously differ in so far that the resulting M[(Dien)Pt(PMEA-N7)]2+ complexes are somewhat less stable, but again Cu2+ and Zn2+ also form with this ligand comparable amounts of the mentioned five-membered chelates. In contrast, both M[(Dien)Pt(PMEA-N1/N7)]2+ complexes differ from the parent M(PMEA) complexes considerably; in the latter instance the formation of the five-membered chelates is of significance for all divalent metal ions studied. The observation that divalent metal-ion binding to the phosphonate group of (Dien)Pt(PMEA-N1) and (Dien)Pt(PMEA-N7) is only moderately inhibited (about 0.2-0.4 log units) by the twofold positively charged (Dien)Pt2+ unit at the adenine residue allows the general conclusion, considering that PMEA is a nucleotide analogue, that this is also true for nucleotides and that consequently participation of, for example, two metal ions in an enzymatic process involving nucleotides is not seriously hampered by charge repulsion.

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Metal ion-binding properties of 9-(4-phosphonobutyl)adenine (dPMEA), a sister compound of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), and quantification of the equilibria involving four Cu(PMEA) isomers

Cited by 36 publications

References 43 publications

Acid-base properties of purine residues and the effect of metal ions: Quantification of rare nucleobase tautomers

Acid-base properties of purine residues and the effect of metal ions: Quantification of rare nucleobase tautomers

Quantification of isomeric equilibria formed by metal ion complexes of 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine (8,8aPMEA) and 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA). Derivatives of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

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