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)

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

doi:10.1007/s00775-004-0591-7

Cited by 13 publications

(8 citation statements)

References 72 publications

(136 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[47] In contrast, divalent transition metal ions are expected [36,37,46] to coordinate not only to N7 but also to N3 in an innersphere manner. Indeed, there are several examples where a kinetically inert Pt II ion coordinates to an adenine N3, [48][49][50] but the corresponding observation has also been made with labile metal ions like Cu II , [51] and if a further suitable guiding binding site, like in several antivirally active nucleotide analogues is available, N3 coordination may become common, [42,52,53] which, knowing the intrinsic basicity of N3, is no real surprise anymore. Inner-sphere binding to N7 is well known [45,47] and has often been observed for adenine nucleotides which undergo macrochelate formation.…”

Section: Resultsmentioning

confidence: 92%

Understanding the Acid–Base Properties of Adenosine: The Intrinsic Basicities of N1, N3 and N7

Kapinos

Operschall

Larsen

et al. 2011

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Adenosine (Ado) can accept three protons, at N1, N3, and N7, to give H(3) (Ado)(3+) , and thus has three macro acidity constants. Unfortunately, these constants do not reflect the real basicity of the N sites due to internal repulsions, for example, between (N1)H(+) and (N7)H(+). However, these macroconstants are still needed for the evaluations and the first two are taken from our own earlier work, that is, pK(H)(H(3))((Ado)) = -4.02 and pK(H)(H(2))((Ado)) = -1.53; the third one was re-measured as pK(H)(H)((Ado)) = 3.64 ± 0.02 (25 °C; I=0.5 M, NaNO(3)), because it is the main basis for evaluating the intrinsic basicities of N7 and N3. Previously, contradicting results had been published for the micro acidity constant of the (N7)H(+) site; this constant has now been determined in an unequivocal manner, and that of the (N3)H(+) site was obtained for the first time. The micro acidity constants, which describe the release of a proton from an (N)H(+) site under conditions for which the other nitrogen atoms are free and do not carry a proton, decrease in the order pk(N7-N1)(N7(Ado)N1·H)) = 3.63 ± 0.02 > pk(N7-N1)(H·N7(Ado)N1) = 2.15 ± 0.15 > pk(N3-N1,N7)(H·N3(Ado)N1,N7) =1.5 ± 0.3, reflecting the decreasing basicity of the various nitrogen atoms, that is, N1>N7>N3. Application of the above-mentioned microconstants allows one to calculate the percentages (formation degrees) of the tautomers formed for monoprotonated adenosine, H(Ado)(+) , in aqueous solution; the results are 96.1, 3.2, and 0.7% for N7(Ado)N1·H(+), (+)H·N7(Ado)N1, and (+)H·N3(Ado)N1,N7, respectively. These results are in excellent agreement with theoretical DFT calculations. Evidently, H(Ado)(+) exists to the largest part as N7(Ado)N1·H(+) having the proton located at N1; the two other tautomers are minority species, but they still form. These results are not only meaningful for adenosine itself, but are also of relevance for nucleic acids and adenine nucleotides, as they help to understand their metal ion-binding properties; these aspects are briefly discussed.

show abstract

Section: Resultsmentioning

confidence: 92%

Understanding the Acid–Base Properties of Adenosine: The Intrinsic Basicities of N1, N3 and N7

Kapinos

Operschall

Larsen

et al. 2011

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…In other words, the formation degree of an isomer involving N3 coordination in Cu(PME2AP) is vanishingly small and thus the isomeric distributions given in Table 8 hold. Considering further that Cu 2+ has the largest affinity to N3, 72, 73 it is evident that the conclusions given in Sections 3.7 and 3.8 hold for all metal ions considered and that for M(PME2AP) complexes only the equilibrium scheme ( 16) is of relevance.…”

Section: Comparison Of the Coordinating Properties Of Pmea And Pme2apmentioning

confidence: 81%

Metal ion-binding properties of 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer of the antiviral nucleotide analogue 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA). Steric guiding of metal ion-coordination by the purine-amino group

et al. 2010

Self Cite

View full text Add to dashboard Cite

The acidity constants of 3-fold protonated 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine, H(3)(PME2AP)(+), and the stability constants of the M(H;PME2AP)(+) and M(PME2AP) complexes with M(2+) = Ca(2+), Mg(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+) or Cd(2+) have been determined by potentiometric pH titrations in aqueous solution (25 degrees C; I = 0.1 M, NaNO(3)). It is concluded that in the M(H;PME2AP)(+) species, the proton is at the phosphonate group and the metal ion at N7 of the purine residue. This "open" form allows macrochelate formation of M(2+) with the monoprotonated phosphonate residue. The formation degree of this macrochelate amounts on average to 64 +/- 13% (3sigma) for those metal ions for which an evaluation was possible (Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+)). The identity of this formation degree indicates that the M(2+)/P(O)(2)(-)(OH) interaction occurs in an outersphere manner. The application of previously determined straight-line plots of log K(M)(M(R-PO(3)))versus pK(H)(H(R-PO(3))) for simple phosph(on)ate ligands, R-PO(3)(2-), where R represents a residue that does not affect metal ion binding, proves that all the M(PME2AP) complexes have larger stabilities than is expected for a sole phosphonate coordination of M(2+). Combination with previous results allows the following conclusions: (i) The increased stability of the M(PME2AP) complexes of Ca(2+), Mg(2+) and Mn(2+) is due to the formation of 5-membered chelates involving the ether-oxygen atom of the -CH(2)-O-CH(2)-PO(3)(2-) residue; the formation degrees of these M(PME2AP)(cl/O) chelates for the mentioned metal ions vary between about 25% (Ca(2+)) to 40% (Mn(2+)). (ii) For the M(PME2AP) complexes of Co(2+), Ni(2+), Cu(2+), Zn(2+) or Cd(2+) next to the mentioned 5-membered chelates a further isomer is formed, namely a macrochelate involving N7, M(PME2AP)(cl/N7). The formation degrees of these macrochelates vary between about 30% (Cd(2+)) and 85% (Ni(2+)). (iii) The most remarkable observation of this study is that the shift of the NH(2) group from C6 to C2 facilitates very significantly macrochelate formation of a PO(3)(2-)-coordinated M(2+) with N7 due to the removal of steric hindrance in the M(PME2AP) complexes. However, any M(2+) interaction with N3 is completely suppressed, thus leading to significantly different coordination patterns than those observed previously with the antivirally active PMEA(2-) species.

show abstract

“…[29][30][31] This also applies for the equipment employed in the potentiometric pH titrations (see also below) and their evaluations, 31 as well as for the experimental procedures regarding the determination of the concentration of the NaOH, ligand, and metal-ionstock solutions. 29,32 2.2. Potentiometric pH Titrations.…”

Section: Methodsmentioning

confidence: 99%

“…The stability constants were calculated 35 considering the species H + , H 2 (PEEA) ( , H(PEEA) -, PEEA 2-, M 2+ , M(H;PEEA) + , and M(PEEA) by using the experimental data at every 0.1 pH unit in the pH range up to a 90% neutralization of H(PEEA) + or until the beginning of the hydrolysis of M(aq) 2+ ; the latter was clear from the titrations without the ligand. However, several of the constants given for the M(H;PEEA) + complexes, especially those for the alkaline earth ion complexes, must be considered as estimates 32 (see Table 2, below) because the formation degree of these species reached only about 3%; the maximum was reached for Mg(H;PEEA) + at 7%. In all of the other instances, the maximum formation degree of M(H;PEEA) + varied between about 5 and 30%.…”

Section: Methodsmentioning

confidence: 99%

Acid−Base and Metal-Ion-Binding Properties of 9-[2-(2-Phosphonoethoxy)ethyl]adenine (PEEA), a Relative of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA). An Exercise on the Quantification of Isomeric Complex Equilibria in Solution

et al. 2005

Self Cite

View full text Add to dashboard Cite

The acidity constants of 3-fold protonated 9-[2-(2-phosphonoethoxy)ethyl]adenine, H3(PEEA)+, and of 2-fold protonated (2-phosphonoethoxy)ethane, H2(PEE), and the stability constants of the M(H;PEEA)+, M(PEEA), and M(PEE) complexes with M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, or Cd2+ have been determined (potentiometric pH titrations; aqueous solution; 25 degrees C; I = 0.1 M, NaNO3). It is concluded that in the M(H;PEEA)+ species, the proton is at the phosphonate group and the metal ion at the adenine residue. The 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 residue that does not affect metal-ion binding, proves that the M(PEEA) complexes of Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ as well as the M(PEE) complexes of Co2+, Cu2+, and Zn2+ have larger stabilities than is expected for a sole phosphonate coordination of M2+. For the M2+ complexes without an enhanced stability (e.g., Mg2+ or Mn2+), it is concluded that M2+ binds in a monodentate fashion to the phosphonate group of the two ligands. Combination of all of the results allows the following conclusions: (i) The increased stability of the Co(PEE), Cu(PEE), Zn(PEE), and Co(PEEA) complexes is due to the formation of six-membered chelates involving the ether-oxygen atom of the aliphatic residue (-CH2-O-CH2CH2-PO3(2-)) of the ligands with formation degrees of about 15-30%. (ii) Cd(PEEA) forms a macrochelate with N7 of the adenine residue (formation degree about 30%); Ni(PEEA) has similar properties. (iii) With Zn(PEEA), both mentioned types of chelates are observed, that is, Zn(PEEA)(cl/O) and Zn(PEEA)(cl/N7), with formation degrees of about 13 and 41%, respectively; the remaining 46% is due to the "open" isomer Zn(PEEA)(op) in which the metal ion binds only to the PO3(2-) group. (iv) Most remarkable is Cu(PEEA) because a fourth isomer, Cu(PEEA)(cl/O/N3), is formed that contains a six-membered ring involving the ether oxygen next to the phosphonate group and also a seven-membered ring involving N3 of the adenine residue with a very significant formation degree of about 50%. Hence, PEEA(2-) is a truly ambivalent ligand, its properties being strongly dependent on the kind of metal ion involved. Comparisons with M2+ complexes formed by the dianions of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and related ligands reveal that five-membered chelates involving an ether-oxygen atom are considerably more stable than the corresponding six-membered ones. This observation offers an explanation of why PMEA is a nucleotide analogue with excellent antiviral properties and PEEA is not.

show abstract

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)

Abstract: 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)

Cited by 13 publications

References 72 publications

Understanding the Acid–Base Properties of Adenosine: The Intrinsic Basicities of N1, N3 and N7

Understanding the Acid–Base Properties of Adenosine: The Intrinsic Basicities of N1, N3 and N7

Metal ion-binding properties of 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer of the antiviral nucleotide analogue 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA). Steric guiding of metal ion-coordination by the purine-amino group

Acid−Base and Metal-Ion-Binding Properties of 9-[2-(2-Phosphonoethoxy)ethyl]adenine (PEEA), a Relative of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA). An Exercise on the Quantification of Isomeric Complex Equilibria in Solution

Contact Info

Product

Resources

About