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 = diethyl enetriamine and PM EA(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+ sit e in H-3[(Dien)-Pt(PMEA-N1)](3+) occurs with a rather low pK(a) (= 0.52 +/- 0.10). The release of the proton from the -P(O)(2)(OH)(-) group (pK(a) = 6 .69 +/- 0.03) in H[(Dien)-Pt(PMEA-N1)](+) is only slightly affected by the N1-coordinated (Dien)Pt2+ unit. Comparison with the acidic properties of th e H[(Dien)Pt(PMEA-N7)](+) species provides evidence that in the (Dien)Pt(PM EA-N7) complex in aqueous solution an intramolecular, outer-sphere macroche late is formed through hydrogen bonds between the -PO32- residue of PMEA(2- ) and a Pt-II-coordinated (Dien)NH, group; its formation degree amounts to about 40%, The stability constants of the M[(Dien)Pt(PMEA- N1)](2+) complex es with M2+ = Mg2+ Ca2+, Ni2+, CU2+ and Zn2+ were measured by potentiometri c pH titrations in aqueous solution at 25 degreesC and I = 0.1M (NaNO3). Ap plication of previously determined straight-line plots of log K(M)((R-PO3)) (M)versus pK(H)((R-PO3))(H) for simple phosph(on)ate ligands, R-PO32-, wher e 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 phosphon ate group with all metal ions studied; in fact, Mg2+, Ca2+ and Ni2+ coordin ate (within the error limits) only to this site. For the Cu[(Dien)Pt(PMEA-N 1)](2+) and Zn[(Dien)Pt(PMEA-NI)](2+) systems also the formation of five-me mbered chelates involving the ether oxygen of the -CH2-O-CH2-PO32- residue could be detected; the formation degrees are about 60 % and 30%, respective ly. The metal-ion-binding properties of the isomeric (Dien)Pt(PMEA-N7) spec ies studied previously differ in so far that the resulting M[(Dien)Pt(PMEA- N7)](2+) complexes are somewhat less stable, but again CU2+ and Zn2+ also f orm with this ligand comparable amounts of the mentioned five-membered chel ates. In contrast, both M[(Dien)Pt(PMEA-N1/ N7)](2+) complexes differ from the parent M(PMEA) complexes considerably; in the latter instance the forma tion of the five-membered chelates is of significance for all divalent meta l ions studied. The observation that divalent metal-ion binding to the phos phonate group of (Dien)Pt(PMEA-NI) and (Dien)Pt(PMEA-N7) is only moderately inhibited (about 0.2 -0.4 log units) by the twofold positively charged (Di en)Pt2+ unit at the adenine residue allows the general conclusion, consider ing that PMEA is a nucleotide analogue, that this is also true for nucleoti des and that consequently participation of, for example, two metal ions in an enzymatic process involving nucleotides is not seriously hampered by cha rge repulsion.