Stability and structure of binary and ternary metal ion complexes in aqueous solution of the quaternary 1-[2-(phosphonomethoxy)ethyl] derivative of 2,4-diaminopyrimidine (PMEDAPy(-)). Properties of an acyclic nucleotide analogue

摘要

The acidity constants of the twofold protonated. quaternary 1-[2-(phosphonomethoxy)ethyl] derivative of 2,4-diaminopyrimidine, H-2(PMEDAPy)(+), were determined by potentiometric pH titrations in aqueous solution (25 degreesC; I = 0.1 M, NaNO3) and compared with the corresponding constants of also twofold protonated. O-phosphonatomethylcholine, H-2(PMCh)(+), an analogue of phosphocholine; the corresponding acidity constants are quite similar. By the same experimental method and under the same conditions the stability constants of the M(PMEDAPy)(+) complexes with the metal ions M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+ and also of the mixed ligand complexes, Cu(Arm)(PMEDAPy)(+), where Arm = Bpy (2,2'-bipyridine) or Phen (1,10-phenanthroline), have also been determined. Application of the 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-, where R represents a residue that does not affect complex formation, proves that the positively charged pyrimidinium residue somewhat inhibits, due to charge repulsion, complex formation with the -PO32- group. In fact, a comparison with previous results obtained for R-CH2CH2-O-CH2-PO32- (=PME-R2-) ligands (R is non-interacting) with the data obtained now for the binary complexes of PMEDAPy(-) shows that for all 10 divalent metal ions studied the inhibition amounts to Deltalog Delta(M/PMEDAPy) = 0.42+/-0.04. This 'constant' repulsive effect is evidence that in the M(PMEDAPy)(+) complexes the ether oxygen does not participate in complex formation; this is different in the M(PME-R) complexes, where five-membered chelates form in equilibrium, the extent being dependent on the kind of metal ion involved. The results for the mixed ligand Cu(Arm)(PMEDAPy)(+) complexes show a significant increase in complex stability of about 0.6 log unit (compared to the stability expected on the basis of the basicity of the phosphonate group), which is due to intramolecular stack formation between the aromatic ring systems of Phen or Bpy and the pyrimidinium moiety of PMEDAPy(-). The formation degree of the stacked isomer in the Cu(Arm)(PMEDAPy)(+) systems is on the order of 70%, though it is somewhat more pronounced with Phen than with Bpy. Comparisons with the Cu(Arm)(N) systems, where N = cytidine 5'-monophosphate (CMP2-) or 1-[2-(phosphonomethoxy)ethyl]cytosine (PMEC2-), reveal that the stacking properties of all three pyrimidine derivatives are similar. An explanation is offered why PMEDAPy(-) shows no biological activity compared to several other closely related acyclic nucleotide analogues, which have antiviral properties. (C) 2003 Elsevier Science Ltd. All rights reserved. [References: 57]