Aspects of the co-ordination chemistry of the antiviral nucleotide analogue, 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP)

The acidity constants of the twofold protonated, acyclic, antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine, H-2(PMEDAP)(+/-), as well as the stability constants of the M(H;PMEDAP)(+) and M(PMEDAP) complexes with the metal ions M2+=Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+, have been determined by potentiometric pH titrations in aqueous solution at I=0.1 M (NaNO3) and 25 degrees C. 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 and comparisons with previous results obtained for the nucleobase-free compound (phosphonomethoxy)ethane, PME, and its derivative, PME-R, where R represents a nucleobase residue without an affinity for metal ions, show that the primary binding site of PMEDAP(2-) is the phosphonate group with all the metal ions studied and that also in all instances 5-membered chelates involving the ether oxygen of the -CH2OCH2PO32- chain are formed. The position of the isomeric equilibria between these chelates, M(PMEDAP)(cl/O), and the 'open' complexes, M(PMEDAP)(op), is determined. In the M2+/PMEDAP(2-) systems with Co2+, Ni2+, Cu2+, and most likely also Zn2+, a third isomer is formed which was detected by comparing the stabilities of the M(PMEDAP) and M(PME-R) complexes; this additional stability enhancement has to be attributed to the 2,6-diaminopurine residue. General considerations as well as H-1 NMR line broadening studies with Cu2+ reveal that in this third isomer a macrochelate is formed in which the phosphonate-bound metal ion interacts in addition with N7 of the purine residue, M(PMEDAP)(cl/N7). The equilibria involving the three isomers are described and quantified; e.g. 19 (+/- 3)% of Cu(PMEDAP) exists as an isomer with a sole phosphonate co-ordination, 38 (+/- 11)% as Cu(PMEDAP)(cl/O) and 43 (+/- 11)% as Cu(PMEDAP)(cl/N7). The corresponding numbers of Ni(PMEDAP) are 33 (+/- 6)% (open), 13 (+/- 8)% (cl/O) and 54 (+/- 10)% (cl/N7). The open and the macrochelated isomers resemble in their structure the corresponding complexes formed by the parent nucleotide adenosine 5'-monophosphate (AMP(2-)). The possible interrelation between the structure of the metal ion complexes in solution and the antiviral properties of PMEDAP and related compounds is discussed.