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, H₃(PME2AP)⁺, and the stability constants of the M(H;PME2AP)⁺ and M(PME2AP) complexes with M²⁺ = Ca²⁺, Mg²⁺, 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;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 M²⁺ with the monoprotonated phosphonate residue. The formation degree of this macrochelate amounts on average to 64 ± 13% (3σ) for those metal ions for which an evaluation was possible (Mn²⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺). The identity of this formation degree indicates that the M²⁺/P(O)₂⁻(OH) interaction occurs in an outersphere manner. The application of previously determined straight-line plots of log K^M_M(R-PO3)versus pK^H_H(R-PO3) for simple phosph(on)ate ligands, R-PO₃²⁻, 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 M²⁺. Combination with previous results allows the following conclusions: (i) The increased stability of the M(PME2AP) complexes of Ca²⁺, Mg²⁺ and Mn²⁺ is due to the formation of 5-membered chelates involving the ether-oxygen atom of the –CH₂–O–CH₂–PO₃²⁻ residue; the formation degrees of these M(PME2AP)_cl/O chelates for the mentioned metal ions vary between about 25% (Ca²⁺) to 40% (Mn²⁺). (ii) For the M(PME2AP) complexes of Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺ or Cd²⁺ 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% (Cd²⁺) and 85% (Ni²⁺). (iii) The most remarkable observation of this study is that the shift of the NH₂ group from C6 to C2 facilitates very significantly macrochelate formation of a PO₃²⁻-coordinated M²⁺ with N7 due to the removal of steric hindrance in the M(PME2AP) complexes. However, any M²⁺ interaction with N3 is completely suppressed, thus leading to significantly different coordination patterns than those observed previously with the antivirally active PMEA²⁻ species.