Solution Structures of Binary and Ternary Metal Ion Complexes of 9‐(5‐Phosphonopentyl)adenine (3′‐deoxa‐PEEA). A Nucleotide Analogue Related to the Antivirally Active 9‐[2‐(Phosphonomethoxy)ethyl]adenine (PMEA)

The acidity constants of the twofold protonated acyclic 9‐(5‐phosphonopentyl)adenine, H 2 (dPEEA) ± , as well as the stability constants of the M(H;dPEEA) + and M(dPEEA) complexes with the metal ions M 2+ = Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Mn 2+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ or Cd 2+ , have been determined by potentiometric pH titrations in aqueous solution at I = 0.1 M (NaNO 3 ) and 25 °C. Application of previously determined straight‐line plots of log K M   M(R‐PO   3 )versus p K H   H(R‐PO   3 )for simple phosph(on)ate ligands, R‐PO 3 2− , where R represents a residue which cannot participate in the coordination process, proves that the primary binding site of dPEEA 2− is the phosphonate group with all the metal ions studied. However, for the M(dPEEA) systems with Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ and Cd 2+ a (in part rather small) stability increase is observed which is due to macrochelate formation with the adenine residue, i.e. most likely with N7. The formation degrees of the macrochelates are 17 ± 15%, 28 ± 10%, 46 ± 12%, 42 ± 28%, and 42 ± 9% (3σ), respectively. This means that in this respect dPEEA 2− resembles the parent nucleotide adenosine 5′‐monophosphate (AMP 2− ) more than its chain‐shortened analogue 9‐(4‐phosphonobutyl)adenine (dPMEA 2− ); indeed, in a first approximation macrochelate formation increases for a given metal ion within the series M(dPMEA) < M(dPEEA) < M(AMP). However, the coordinating properties of all three mentioned ligands differ significantly from those of the antivirally active 9‐[2‐(phosphonomethoxy)ethyl]adenine (PMEA 2− ) which, due to the presence of an ether oxygen in the aliphatic side chain, has a different coordination chemistry which involves five‐membered chelates with the ether oxygen atom. In addition, 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 H(dPEEA) − or dPEEA 2− species were also measured. Detailed stability constant comparisons reveal that in the monoprotonated ternary Cu(Arm)(H;dPEEA) + complexes the proton is at the phosphonate group and that stacking between Cu(Arm) 2+ and H(dPEEA) − plays a significant role. For the Cu(Arm)(dPEEA) complexes a large increase in complex stability (compared to the stability expected on the basis of the basicity of the phosphonate group) is observed, which is due to intramolecular stack formation between the aromatic ring systems of Phen or Bpy and the purine moiety of dPEEA 2− . The formation degree of the stacked isomers is in the order of 65 to 80%. Comparisons of the Cu(Arm)(PA) systems, where PA 2− = dPEEA 2− , dPMEA 2− or AMP 2− , reveal that here dPEEA 2− resembles its parent AMP 2− less closely than dPMEA 2− does. The biological implications of these results, including antiviral activities, are shortly discussed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)