Properties of the ternary (Dien)Pt(PMEA-N7) complex containing diethylenetriamine (Dien) and the antiviral 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). Synthesis, biological screening, acid-base behaviour, and metal ion-binding in aqueous solution

The synthesis of (Dien)Pt(PMEA-N7), where Dien = diethylenetriamine and PME A(2-) = dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is described. No u seful biological activity could be discovered for this complex which is in contrast to the known antiviral properties of PMEA itself. The acidity cons tants of the twofold protonated H-2[(Dien)Pt(PMEA-N7)](2+) complex were det ermined (UV spectrophotometry and potentiometric pH titration): The release of the proton from the -P(O)(2)(OH)(-) group is only slightly affected by the N7-coordinated (Dien)Pt2+ unit, whereas the acidity of the (NI)H+ site is strongly enhanced. The stability constants of the M[(Dien)Pt(PMEA-N7)](2 +) complexes with the metal ions M2+ = Mg2+, Ca2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ were measured by potentiometric pH titrations in aqueous sol ution at 25 degreesC and I = 0.1 M (NaNO3); Application of previously deter mined straightline plots of log K-M(R-PO3)(M) versus PKH(R-PO3)H for simple phosph(on)ate ligands, R-PO32- where R represents a non-inhibiting residue without an affinity for metal ions, proves that the primary binding site o f the complex-ligand, (Dien)Pt(PMEA-N7), with all the metal ions studied is the phosphonate group; in most instances the expected stability is actuall y reduced by about 0.4 log units due to the N7-bound (Dien)Pt2+ unit. Only for the Cu[(Dien)Pt(PMEA-N7)](2+) and the Zn[(Dien)Pt(PMEA-N7)](2+) systems the formation of some 5-membered chelates involving the ether oxygen atom of the -CH2-O-CH2-PO32- residue could be detected; the formation degrees ar e 52 +/- 9% and 32 +/- 14%, respectively. The metal ion-binding properties of (Dien)Pt(PMEA-N7) differ considerably from those of PMEA(2-), yet they a re relatively similar to those of pyrimidine-nucleoside 5'-monophosphates. The structures of the various complex species in solution are discussed and compared.