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.
ABSTRACT 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.
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ABSTRACT: The acidity constants of 3-fold protonated 9-[2-(phosphonomethoxy)ethyl]-2-amino-6-dimethylaminopurine, H3(PME2A6DMAP)+ are considered, and the stability constants of the M(H;PME2A6DMAP)+ and M(PME2A6DMAP) complexes with M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+ have been determined by potentiometric pH titrations in aqueous solution (25°C; I = 0.1 M, NaNO3). It is concluded that in the M(H;PME2A6DMAP)+ species, the proton is at the phosphonate group and that also the metal ion is coordinated (mainly in an outersphere manner) at this site. There is no indication that the purine residue participates in a significant extent in M2+ binding in the M(H;PME2A6DMAP)+ species. This contrasts, e.g., with the corresponding complexes formed by the parent compound 9-[2-(phosphonomethoxy)ethyl]adenine, that is, M(H;PMEA)+, where M2+ is mainly coordinated at the adenine residue. The application of previously determined straight-line plots of log versus for simple phosph(on)ate ligands, R-PO , where R represents a residue that does not affect metal ion binding, proves that all the M(PME2A6DMAP) complexes have larger stabilities than is expected for a sole phosphonate coordination of M2+. Comparison with previous results obtained for M(PME-R) complexes, where R is a non-coordinating residue of the (phosphonomethoxy)ethane chain, allows the conclusion that the increased stability of all the M(PME2A6DMAP) complexes is due to the formation of 5-membered chelates involving the ether-oxygen atom of the –CH2–O–CH2–PO residue: The formation degrees of these M(PME2A6DMAP)cl/O chelates, which occur in intramolecular equilibria for the mentioned metal ions, vary between about 20% (Sr2+, Ba2+) and 50% (Zn2+, Cd2+), going up to 67% (Cu2+) in the maximum. Any M2+ interaction with N3 or N7 of the purine moiety, as it occurs in M(PMEA) complexes, is suppressed by the (C2)NH2 and (C6)N(CH3)2 substituents, respectively. This observation, together with the previously determined stacking properties, offers an explanation why PME2A6DMAP2– has remarkable therapeutic effects.Canadian Journal of Chemistry 08/2014; · 1.01 Impact Factor
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ABSTRACT: The role that the amino group plays in the metal ion (M2+) binding properties of the adenine residue is of great relevance because this residue occurs widely in nature. It is the aim of this review to evaluate this role. We consider first several 9-methylpurine derivatives with amino and methyl substituents at various positions: the data indicate that substituents at C6 inhibit M2+ binding at both, the N1 and N7 sites. To separate these effects we use (i) o-amino(methyl)pyridines as models for the pyrimidine part of the adenine residue, i.e., for N1, and (ii) benzimidazole derivatives regarding the properties of N7. The inhibiting effects of ortho-amino and ortho-methyl groups on N1 of pyridines are identical, which agrees with the fact that such an amino group has no basic properties at all. This is different with 1-methyl-4-aminobenzimidazole (MABI) (9-methyl-1,3-dideazaadenine) and 1,4-dimethylbenzimidazole (DMBI) (6,9-dimethyl-1,3-dideazapurine) because the amino group in MABI still has some basic properties and thus, its steric inhibition is somewhat smaller than that of the methyl group in DMBI. It is suggested that the methyl group in DMBI mimics the steric effects of (C6)NH2 upon (N7)-M2+ coordination in the adenine residue. The evaluation of the N1 versus N7 dichotomy for 2,9-dimethylpurine, 2-amino-9-methylpurine, and 6-amino-9-methylpurine (9-methyladenine) reveals that the (N7)-M2+ isomer dominates. It is further suggested that the (C6)NH2 adenine group may act as a proton donor and the O atom of a coordinated water molecule as acceptor. The metal ion-binding properties of the two acyclic nucleotide analogues 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA) and 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), which are structural isomers due to the shift of the (C6)NH2 group in PMEA to the C2 site in PME2AP, fit into the indicated coordination patterns. In the monoprotonated species M(H;PMEA)+ and M(H;PME2AP)+ the proton is located at the phosphonate group and M2+ at N7. However, the M(H;PME2AP)+ complexes are considerably more stable than the M(H;PMEA)+ ones: indeed, the steric effect on N1 is the same in both types of complexes, but the one on N7 has disappeared in M(H;PME2AP)+. Furthermore, there is evidence that the (N7)-coordinated M2+ interacts with the P(O)2(OH)− group in an outersphere manner leading to practically identical formation degrees of the macrochelates formed with Mn2+, Co2+, Ni2+, Cu2+ or Zn2+ [on average 65 ± 15% (3σ)]. The coordination chemistry of PMEA2− and PME2AP2− differs for the 3d ions as well, whereas for the alkaline earth ions, which are primarily coordinated (like all other M2+) to the phosphonate group, 5-membered chelates form involving the ether O of the –CH2CH2–O–CH2–PO32− residue. In contrast, Co2+, Ni2+, and Cu2+ form with PMEA2− a further isomer, which involves next to the ether O also N3; macrochelates involving N7 and the phosphonate-coordinated M2+ are minority species, but for Ni2+ and Cu2+ they occur and formation degrees of all four isomers could be determined. In the M(PME2AP) complexes a N3 interaction practically does not occur; macrochelate formation of the phosphonate-coordinated M2+ with N7, which is the dominating species for Co2+, Ni2+, Cu2+ or Zn2+ is important here. The possible interrelations between M2+ coordination and the antiviral activity of the two acyclic nucleotide analogues, PMEA being especially active, are discussed shortly.Coordination Chemistry Reviews 01/2012; 256(s 1–2):260–278. · 12.10 Impact Factor
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ABSTRACT: This communication describes the synthesis and structure of zinc, cadmium, and mercury complexes of modified N9-substituted 2-aminopurine (2AP) analogues. 2AP is an inherently fluorescent heterocyclic nucleobase with wide applications in biochemical reactions. Herein, we report a one-dimensional (1D) polymeric helical chain and discrete arrangements for zinc complexes [C8H11N5Cl2Zn] (1) and [C12H15N5O5Zn] (2), a 1D polymeric helical chain for a Cd complex [C8H11CdI2N5] (3), and a unique example of supported 2AP-Hg(II) two-dimensional clusters [C16H21Cl6Hg3N10] (4). The photoluminescence properties of free ligand L and complexes 1–4 are also presented.Crystal Growth & Design 06/2013; 13(7):2716–2721. · 4.56 Impact Factor