Metal Ion-Binding Properties of 9-[(2-Phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an Isomer of the Antiviral Nucleotide Analogue 9-[(2-Phosphonometh¬oxy)ethyl]adenine (PMEA) : Steric Guiding of Metal Ion-Coordination by the Purine-Amino Group

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 KMM(R-PO3)versus pKHH(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.