Extent of Intramolecular π Stacks in Aqueous Solution in Mixed‐Ligand Copper(II) Complexes Formed by Heteroaromatic Amines and 1‐[2‐(Phosphonomethoxy)ethyl]cytosine (PMEC), a Relative of Antivirally Active Acyclic Nucleotide Analogues (Part 72)[1, 2]

Abstract

AbstractStability constants of the ternary Cu(Arm)(H;PMEC)+ and Cu(Arm)(PMEC) complexes {PMEC2– = dianion of 1‐[2‐(phosphonomethoxy)ethyl]cytosine, Arm = 2, 2′‐bipyridine (Bpy) or 1, 10‐phenanthroline (Phen)} were measured by potentiometric pH titrations (aq. sol.; 25 °C; I = 0.1 M, NaNO3) and compared with those of Cu(Arm)(H;PMEA)+ and Cu(Arm)(PMEA) {PMEA2– = dianion of 9‐[2‐(phosphonomethoxy)ethyl]adenine}, and related species. The basicity of the terminal phosphonate group is similar in PMEC2– and PMEA2–. Stability‐constant comparisons reveal, that in the monoprotonated ternary Cu(Arm)(H;PMEC)+ complexes H+ is at the phosphonate group, that the ether oxygen atom of the –CH2–O–CH2–P(O)–2(OH) residue participates, next to the P(O)–2(OH) group, in Cu(Arm)2+ coordination, and that π–π stacking between the aromatic rings of Cu(Arm)2+ and the pyrimidine moiety is important. The Cu(Arm)(PMEC) complexes are considerably more stable than the corresponding Cu(Arm)(R–PO3) species, where R–PO2–3 is a phosph(on)ate with a group R unable to interact intramolecularly. The stability enhancements are mainly attributed to intramolecular stacks and, to a smaller extent, to the formation of five‐membered chelates involving the ether oxygen atom of the –CH2–O–CH2–P(O)2–3 residue of PMEC2–. Analysis of the intramolecular equilibria reveals that ca. 10 % of the isomeric ternary complexes exist with Cu(Arm)2+ solely coordinated to the phosphonate group, ca. 25 % as a five‐membered chelate involving the ether oxygen, and ca. 65 % with an intramolecular π–π stack between the pyrimidine moiety of PMEC2– and the rings of Bpy or Phen. For a given Cu(Arm)2+ the stacking intensity increases from PMEC2– to PMEA2–. It seems feasible that the reduced stacking intensity of PMEC2–, together with a different hydrogen bonding pattern, leads to a different orientation of the cytosine residue (compared to the adenine moiety) in the active site of the nucleic acid polymerases, thus resulting in a reduced antiviral activity of PMEC compared to PMEA.