Extent of Intramolecular pi 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)

作者：Blindauer Claudia A; Sigel Astrid; Operschall Bert P; Holy Antonin; Sigel Helmut^*

来源：Zeitschrift fur Anorganische und Allgemeine Chemie, 2013, 639(8-9): 1661-1673.

DOI：10.1002/zaac.201300095

• Nucleotide analogues
• Antivirals
• Complex stabilities
• Isomers
• Equilibria
• Mixed ligand complexes

Stability constants of the ternary Cu(Arm)(H;PMEC)(+) and Cu(Arm)(PMEC) complexes {PMEC2- = dianion of 1-[2-(phosphonomethoxy)ethyl]cytosine, Arm = 2,2%26apos;-bipyridine (Bpy) or 1,10-phenanthroline (Phen)} were measured by potentiometric pH titrations (aq. sol.; 25 degrees C; I = 0.1 M, NaNO3) and compared with those of Cu(Arm)(H;PMEA)(+) and Cu(Arm)(PMEA) {PMEA(2-) = dianion of 9-[2-(phosphonomethoxy)ethyl]adenine}, and related species. The basicity of the terminal phosphonate group is similar in PMEC2- and PMEA(2-). 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 pi-pi 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-PO32- 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)(3)(2-) 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 pi-pi 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 PMEA(2-). 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.

• 出版日期2013-7