Metal‐ion‐coordinating properties of various phosphonate derivatives, including 9−[2−(phosphonylmethoxy)ethyl]adenine (PMEA) – an adenosine monophosphate (AMP) analogue with antiviral properties

Abstract

AbstractThe stability constants of the 1:1 complexes formed between Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, (in part) Zn2+, or Cd2+ and (phosphonylmethoxy)ethane (PME2−) or 9−[2−(phosphonylmethoxy)ethyl]adenine (PMEA2−) were determined by potentiometric pH titration in aqueous solution (I = 0.1M, NaNO3; 25°). The experimental conditions were carefully selected such that self‐association of the adenine derivative PMEA and of its complexes was negligibly small; i.e., it was made certain that the properties of the monomeric [M(PMEA)] complexes were studied. Recent measurements with simple phosphate monoesters, R–MP2– (where R is a non‐coordinating residue; S. S. Massoud, H. Sigel, Inorg. Chem. 1988, 27, 1447), were used to show that analogously simple phosphonates (RPO) – we studied now the complexes of methyl phosphonate and ethyl phosphonate – fit on the same log K/logK vs. pK/ pK straight‐line plots. With these reference lines, it could be demonstrated that for all the [M(PME)] complexes with the mentioned metal ions an increased complex stability is measured; i.e., a stability higher than that expected for a sole phosphonate coordination of the metal ion. This increased stability is attributed to the formation of five‐membered chelates involving the ether oxygen present in the OCH2PO residue of PME2− (and PMEA2−); the formation degree of the five‐membered [M(PME)] chelates varies between ca. 15 and 40% for the alkaline earth ions and ca. 35 to 65% for 3d ions and Zn2+ or Cd2+. Interestingly, for the [M(PMEA)] complexes within the error limits exactly the same observations are made indicating that the same five‐membered chelates are formed, and that the adenine residue has no influence on the stability of these complexes, with the exception of those with Ni2+ and Cu2+. For these two metal ions, an additional stability increase is observed which has to be attributed to a metal ion‐adenine interaction giving thus rise to equilibria between three different [M(PMEA)] isomers. These equilibria are analyzed, and for [Cu(PMEA)] it is calculated that 17(±3)% exist as an isomer with a sole Cu2+‐phosphonate coordination, 34(±10)% form the mentioned five‐membered chelate involving the ether oxygen, and the remaining 49(±10)% are due to an isomer containing also a Cu2+‐adenine interaction. Based on various arguments, it is suggested that this latter isomer contains two chelate rings which result from a metal‐ion coordination to the phosphonate group, the ether oxygen, and to N(3) of the adenine residue. For [Ni(PMEA)], the isomer with a Ni2+‐adenine interaction is formed to only 22(±13)%; for [Cd(PMEA)] and the other [M(PMEA)] complexes if at all, only traces of such an isomer are occurring. In addition, the [M(PMEA)] complexes may be protonated leading to [M(H·PMEA)]+ species in which the proton is mainly at the phosphonate group, while the metal ion is bound in an adenosine‐type fashion to the nucleic base residue. Finally, the properties of [M(PMEA)] and [M(AMP)] complexes are compared, and in this connection it should be emphasized that the ether oxygen which influences so much the stability and structure of the [M(PMEA)] complexes in solution is also crucial for the antiviral properties of PMEA.