Steric Guiding of Metal Ion Binding to a Purine Residue by a Non-Coordinating Amino Group: Examplified by 9-[(2-Phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an Isomer of the Antiviral Nucleotide Analogue 9-[(2-Phosphonomethoxy)ethyl]adenine (PMEA), and by Related Compounds.

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 phosphon 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 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