Intramolecular π-π stacking interactions in aqueous solution in mixed-ligand copper(II) complexes formed by heteroaromatic amines and the nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer of the antivirally active 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

Abstract The stability constants of the mixed-ligand complexes formed between Cu(Arm) 2+ , where Arm = 2,2′-bipyridine (Bpy) or 1,10-phenanthroline (Phen), and the monoanion or the dianion of 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), a structural isomer of the antivirally active 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), were determined by potentiometric pH titrations in aqueous solution at 25 °C and I  = 0.1 M (NaNO 3 ). Detailed stability constant comparisons reveal that in the monoprotonated ternary Cu(Arm)(H;PME2AP) + complexes the proton is at the phosphonate group and that stacking between Cu(Arm) 2+ and H(PME2AP) − plays a significant role. The ternary Cu(Arm)(PME2AP) complexes are considerably more stable than the corresponding Cu(Arm)(R–PO 3 ) species, where R – PO 3 2 - represents a phosph(on)ate ligand with a group R that is unable to participate in any kind of interaction within the complexes. The increased stability is attributed to intramolecular stack formation in the Cu(Arm)(PME2AP) complexes and also, to a smaller extent, to the formation of 5-membered chelates involving the ether–oxygen present in the – CH 2 – O – CH 2 – PO 3 2 - residue of PME2AP 2− . This latter interaction was previously quantified by studying ternary Cu(Arm)(PME) complexes (PME 2−  = dianion of (phosphonomethoxy)ethane), which can form the 5-membered chelates but where no intramolecular ligand–ligand stacking is possible. Application of these results allows a quantitative analysis of the intramolecular equilibria involving three structurally different Cu(Arm)(PME2AP) species; e.g., about 5% of the Cu(Bpy)(PME2AP) system exist with the metal ion solely coordinated to the phosphonate group, 15% as a 5-membered chelate involving the ether–oxygen atom of the – CH 2 – O – CH 2 – PO 3 2 - residue, and 80% with an intramolecular π–π stack between the purine moiety of PME2AP 2− and the aromatic rings of Bpy. Finally, comparison of the stacking properties of PME2AP 2− and PMEA 2− in their ternary complexes reveals that stacking is somewhat more pronounced in the Cu(Arm)(PMEA) than in the Cu(Arm)(PME2AP) species. Speculatively, this reduced stacking intensity, together with a different hydrogen-bonding pattern, could well lead to a different positioning of the 2-aminopurine moiety (compared to the adenine residue) in the active site cavity of nucleic acid polymerases and thus be responsible for the reduced antiviral activity of PME2AP compared with that of PMEA.