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)

Abstract

The synthesis of (Dien)Pt(PMEA-N1), where Dien = diethylenetriamine and PMEA2- = dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is described. The acidity constants of the threefold protonated H3[(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 H4[(Dien)Pt(PMEA-N1)]3+ occurs with a rather low pKa (= 0.52+/-0.10). The release of the proton from the -P(O)2(OH) group (pKa = 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 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 -PO3(2-) residue of PMEA2- and a PtII-coordinated (Dien)NH2 group; its formation degree amounts to about 40%. The stability constants of the M[(Dien)Pt(PMEA-N1)]2+ complexes with M2+ = Mg2+, Ca2+, Ni2+, Cu2+ and Zn2+ were measured by potentiometric pH titrations in aqueous solution at 25 degrees C and I = 0.1 M (NaNO3). Application 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-PO3(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, Mg2+, Ca2+ and Ni2+ 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 -CH2-O-CH2-PO3(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 Cu2+ and Zn2+ 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)Pt2+ 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.

Complex Formation of Nickel(II) with Sugar Residues, Nucleobases, Phosphates, Nucleotides, and Nucleic Acids

“…Coordination of (Dien)Pt 2ϩ either to N1 [182] or to N7 [183] leads, if monoprotonated, to the complexes H[(Dien)Pt(PMEA-N1)] ϩ and H[(Dien)Pt(PMEA-N7)] ϩ . Acidifi cation of the P(O) 2 (OH) Ϫ group by Pt 2ϩ at N1 gives ∆pK a/N1 ϭ 0.21 ± 0.03 (based on pK H H(PMEA) ϭ 6.90 ± 0.01) and by Pt 2ϩ at N7 ∆pK a/N7 ϭ 0.44 ± 0.01 [182]. The higher acidity of H[(Dien)Pt(PMEA-N7) ϩ provides evidence, that in the (Dien)Pt(PMEA-N7) complex in aqueous solution an intramolecular, outersphere macrochelate is formed through hydrogen bonds between the PO 3 2Ϫ residue of PMEA 2Ϫ and a Pt(II)-coordinated (Dien)-NH 2 group.…”

“…It needs to be mentioned that, in all these cases, including the Ni 2ϩ systems, no indication for the existence of Equilibrium (34) (see Section 7.4) was observed, i.e., the ether oxygen of the 'aliphatic' side chain of PMEA 2Ϫ does no longer participate in M 2ϩ binding. The only exceptions here are the corresponding Cu 2ϩ and Zn 2ϩ complexes where the fi ve-membered chelates still form to some extent [182].…”

“…Coordination of (Dien)Pt 2ϩ either to N1 [182] or to N7 [183] leads, if monoprotonated, to the complexes H[(Dien)Pt(PMEA-N1)] ϩ and H[(Dien)Pt(PMEA-N7)] ϩ . Acidifi cation of the P(O) 2 (OH) Ϫ group by Pt 2ϩ at N1 gives ∆pK a/N1 ϭ 0.21 ± 0.03 (based on pK H H(PMEA) ϭ 6.90 ± 0.01) and by Pt 2ϩ at N7 ∆pK a/N7 ϭ 0.44 ± 0.01 [182].…”

“…The higher acidity of H[(Dien)Pt(PMEA-N7) ϩ provides evidence, that in the (Dien)Pt(PMEA-N7) complex in aqueous solution an intramolecular, outersphere macrochelate is formed through hydrogen bonds between the PO 3 2Ϫ residue of PMEA 2Ϫ and a Pt(II)-coordinated (Dien)-NH 2 group. This formation amounts to about 40% and is in accord with several other related observations [182].…”

“…The macrochelate mentioned also offers at least a partial explanation for the somewhat different metal ion affi nities, including Ni 2ϩ , of the phosphonate groups of (Dien)Pt(PMEA-N1) and (Dien)Pt(PMEA-N7) which amount on average to log D N1/av ϭ Ϫ0.17 ± 0.06 and log D N7/av ϭ Ϫ0.42 ± 0.04 [182]. This inhibition is due to charge repulsion of the adenine-coordinated (Dien)Pt 2ϩ and the M 2ϩ coordinated at the PO 3 2Ϫ group.…”