Metal Ion‐Coordinating Properties in Aqueous Solutions of the Antivirally Active Nucleotide Analogue (S)‐9‐[3‐Hydroxy‐2‐(phosphonomethoxy)propyl]adenine (HPMPA) – Quantification of Complex Isomeric Equilibria

Abstract

Acyclic nucleoside phosphonates are of medical relevance and deserve detailed chemical characterization. We focus here on (S)‐9‐[3‐hydroxy‐2‐(phosphonomethoxy)propyl]adenine (HPMPA) and include for comparison 9‐[2‐(phosphonomethoxy)ethyl]adenine (PMEA), as well as the nucleobase‐free (phosphonomethoxy)ethane (PME) and (R)‐hydroxy‐2‐(phosphonomethoxy)propane (HPMP). The acidity constants of H3(HPMPA)+ were determined and compared with those of the related phosph(on)ate derivatives; they are also needed to understand the properties of the metal ion complexes. Given that in vivo nucleotides and their analogues participate in reactions typically as divalent metal ion (M2+) complexes, the stability constants of the M(H;HPMPA)+ and M(HPMPA) species with M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ were measured. Comparisons between the results for HPMPA2– and the previous data for PMEA2–, HPMP2– and PME2– revealed that for most M(HPMPA) complexes the enhanced stability (the enhancement relative to the stability of a simple phosphonate‐M2+ coordination), can solely be explained by the formation of 5‐membered chelates involving the ether oxygen. These chelates occur in equilibrium with simple ′open′ phosphonate‐M2+ species, the phosphonate group being the primary binding site. The only exceptions are the M(HPMPA) complexes of Ni2+, Cu2+, and Zn2+, which show an additional stability enhancement; in these instances not only the indicated 5‐membered chelates are formed, but M2+ coordinates in addition to N3 of the adenine residue forming a 7‐membered chelate ring. This observation regarding N3 is important because it emphasizes the metal ion affinity of this site (which is often ignored). Note that in the DNA double helix N3 is exposed to the solvent in the minor groove. The stability data for the monoprotonated M(H;HPMPA)+ complexes suggest that these carry H+ at the phosphonate group whereas M2+ is partly at the nucleobase and partly also at the phosphonate group. The ratios of these isomers depend on the metal ion involved, e.g., for Cu(H;HPMPA) the ratio of the isomers is about 1:1.