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

Abstract

The acidity constants of the twofold protonated, acyclic, antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine, H₂(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 °C. Application of previously determined straight-line plots of log K ^M_M(R-PO3)versus pK ^H_H(R-PO3) 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 –CH₂OCH₂PO₃^2– 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 ¹H 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.