Extent of intramolecular π stacks in aqueous solution in mixed-ligand copper(II) complexes formed by heteroaromatic amines and the anticancer and antivirally active 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG). A comparison with related acyclic nucleotide

The acyclic nucleoside phosphonate (ANP2−) 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) is anticancer and antivirally active. The acidity constants of the threefold protonated H3(PMEG)+ were determined by potentiometric pH titrations (aq. sol.; 25 °C; I = 0.1 M, NaNO3). Under the same conditions and by the same method, the stability constants of the binary Cu(H;PMEG)+ and Cu(PMEG) complexes as well as those of the ternary ones containing a heteroaromatic N ligand (Arm), that is, of Cu(Arm)(H;PMEG)+ and Cu(Arm)(PMEG), where Arm = 2,2′-bipyridine (Bpy) or 1,10-phenanthroline (Phen), were measured. The corresponding equilibrium constants, taken from our earlier work for the systems with 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP) as well as those for Cu(PME) and Cu(Arm)(PME), where PME2− = (phosphonomethoxy)ethane = (ethoxymethyl)phosphonate, were used for comparisons. These reveal that in the monoprotonated ternary Cu(Arm)(H;PE)+ complexes, the proton and Cu(Arm)2+ are at the phosphonate group; the ether oxygen of the –CH2–O–CH2–P(O)2−(OH) residue also participates to some extent in Cu(Arm)2+ coordination. Furthermore, the coordinated Cu(Arm)2+ forms a bridge with the purine moiety undergoing π–π stacking which is more pronounced with H·PMEDAP− than with H·PMEA−. Most intense is π stack formation (st) with the guanine residue of H·PMEG−; here the bridged form Cu(Arm)(H·PMEG)st+ occurs next to an open (op), unbridged (binary) stack, formulated as Cu(Arm)2+/(H·PMEG)op−. The unprotonated and neutral ternary Cu(Arm)(PE) complexes are considerably more stable than the corresponding Cu(Arm)(R-PO3) species, where R-PO32− represents a phosph(on)ate ligand with a group R that is unable to participate in any intramolecular interaction. The observed stability enhancements are mainly due to intramolecular stack formation (st) between the aromatic rings of Arm and the purine residue in the Cu(Arm)(PE) complexes and also, to a smaller extent, to the formation of five-membered chelates involving the ether oxygen of the –CH2–O–CH2–PO32− residue (cl/O) of the PE2− species. The quantitative analysis of the intramolecular equilibria reveals three structurally different Cu(Arm)(PE) isomers; e.g., of Cu(Phen)(PMEG) ca. 1.1% exist as Cu(Phen)(PMEG)op, 3.5% as Cu(Phen)(PMEG)cl/O, and 95% as Cu(Phen)(PMEG)st. Comparison of the various formation degrees reveals that within a given Cu(Arm)(PE) series the stacking tendency decreases in the order PMEG2− ⩾ PMEDAP2− > PMEA2−. Furthermore, stacking is more pronounced in the acyclic Cu(Arm)(PE) complexes compared with that in the Cu(Arm)(NMP) species, where NMP2− = corresponding parent (2′-deoxy)nucleoside 5′-monophosphate. Here is possibly one of the reasons for the biological activity of the ANPs. One is tempted to speculate that the pronounced stacking tendency of PMEG2−, together with a different H-bonding pattern, leads to enhanced binding in the active site of nucleic acid polymerases, thus being responsible for the pronounced anticancer and antiviral activity of PMEG.

The guanine residue of 9-[2-(phosphonomethoxy)ethyl]guanine leads to intense intramolecular stacks in the ternary complex formed with Cu(1,10-phenanthroline)2+ (aqueous solution). Stacking is more pronounced than with the adenine derivative. The formation degrees of the three isomers, PO32−-coordination only, five-membered chelate with the ether-O, and the intramolecular guanine/phenanthroline stack, are determined.Figure optionsDownload as PowerPoint slide