Formation of Ternary Complexes by Coordination of (Diethylenetriamine)Platinum( II ) to N1 or N7 of the Adenine Moiety of the Antiviral Nucleotide Analogue 9‐[2‐(Phosphonomethoxy)ethyl]adenine (PMEA): Comparison of the Acid–Base and Metal‐Ion‐Binding Properties of PMEA, (Dien)Pt(PMEA‐ N1 ), and (Dien)Pt(PMEA‐ N7 )

The synthesis of (Dien)Pt(PMEA‐ N1 ), where Dien=diethylenetriamine and PMEA 2− =dianion of 9‐[2‐(phosphonomethoxy)ethyl]adenine, is described. The acidity constants of the threefold protonated H 3 [(Dien)Pt(PMEA‐ N1 )] 3+ complex were determined and in part estimated (UV spectrophotometry and potentiometric pH titration): The release of the proton from the (N7)H + site in H 3 [(Dien)Pt(PMEA‐ N1 )] 3+ occurs with a rather low p K a (=0.52±0.10). The release of the proton from the ‐P(O) 2 (OH) − group (p K a =6.69±0.03) in H[(Dien)Pt(PMEA‐ N1 )] + is only slightly affected by the N1‐coordinated (Dien)Pt 2+ unit. Comparison with the acidic properties of the H[(Dien)Pt(PMEA‐ N7 )] + species provides evidence that in the (Dien)Pt(PMEA‐ N7 ) complex in aqueous solution an intramolecular, outer‐sphere macrochelate is formed through hydrogen bonds between the ‐PO $\rm{_{3}^{2-}}$ residue of PMEA 2− and a Pt II ‐coordinated (Dien)‐NH 2 group; its formation degree amounts to about 40 %. The stability constants of the M[(Dien)Pt(PMEA‐ N1 )] 2+ complexes with M 2+ =Mg 2+ , Ca 2+ , Ni 2+ , Cu 2+ and Zn 2+ were measured by potentiometric pH titrations in aqueous solution at 25 °C and I =0.1  M (NaNO 3 ). Application of previously determined straight‐line plots of log K $\rm{^{{M}}_{{M(R{\scriptscriptstyle-}PO_3)}}}$ versus p K $\rm{^{{H}}_{{H(R{\scriptscriptstyle-}PO_3)}}}$ for simple phosph(on)ate ligands, R‐PO $\rm{_{3}^{2-}}$ , where R represents a non‐inhibiting residue without an affinity for metal ions, proves that the primary binding site of (Dien)Pt(PMEA‐ N1 ) is the phosphonate group with all metal ions studied; in fact, Mg 2+ , Ca 2+ and Ni 2+ coordinate (within the error limits) only to this site. For the Cu[(Dien)Pt(PMEA‐ N1 )] 2+ and Zn[(Dien)Pt(PMEA‐ N1 )] 2+ systems also the formation of five‐membered chelates involving the ether oxygen of the −CH 2 −O−CH 2 −PO $\rm{_{3}^{2-}}$ residue could be detected; the formation degrees are about 60 % and 30 %, respectively. The metal‐ion‐binding properties of the isomeric (Dien)Pt(PMEA‐ N7 ) species studied previously differ in so far that the resulting M[(Dien)Pt(PMEA‐ N7 )] 2+ complexes are somewhat less stable, but again Cu 2+ and Zn 2+ also form with this ligand comparable amounts of the mentioned five‐membered chelates. In contrast, both M[(Dien)Pt(PMEA‐ N1 / N7 )] 2+ complexes differ from the parent M(PMEA) complexes considerably; in the latter instance the formation of the five‐membered chelates is of significance for all divalent metal ions studied. The observation that divalent metal‐ion binding to the phosphonate group of (Dien)Pt(PMEA‐ N1 ) and (Dien)Pt(PMEA‐ N7 ) is only moderately inhibited (about 0.2–0.4 log units) by the twofold positively charged (Dien)Pt 2+ unit at the adenine residue allows the general conclusion, considering that PMEA is a nucleotide analogue, that this is also true for nucleotides and that consequently participation of, for example, two metal ions in an enzymatic process involving nucleotides is not seriously hampered by charge repulsion.