Complex Formation of the Antiviral 9-[2-(Phosphonomethoxy)Ethyl]Adenine (PMEA) and of Its N 1, N 3, and N 7 Deaza Derivatives with Copper(II) in Aqueous Solution

The stability constants of the 1:1 complexes formed between Cu2+ and the anions of the N 1, N 3, and N 7 deaza derivatives of 9‐[2‐(phosphonomethoxy)‐ethyl]adenine (PA2‐), Cu(H;PA)+ and Cu(PA), were determined by potentiometric pH titration in aqueous solution (25 °C; I = 0.1 M, NaNO3) and compared with previous results for 9‐[2‐(phosphonomethoxy)ethyl]adenine (PMEA2‐) and (phosphonomethoxy)ethane (PME2‐). A microconstant scheme reveals that in Cu(H;PA)+ Cu2+ is coordinated to the nucleobase, H+ being at the phosphonate group, in about 90% of the Cu(H;PMEA)+ and Cu(H;1‐deaza‐PMEA)+ species, but only in about 37% and 12% of the corresponding complexes with H(3‐deaza‐PMEA)‐ and H(7‐deaza‐PMEA)‐, respectively. Straight‐line plots of log KCuCu(R–PO3) versus pKHH(R–PO3) for simple phosph(on)ate ligands show that all the Cu(PA) complexes, including those with PMEA2‐ and PME2‐, are more stable than expected simply from the basicity of the ‐PO2‐ group; to some extent five‐membered chelates (Cu(PA)cl/O) involving the ether oxygen of the ‐CH2–O–CH2–PO2‐3 chain are formed, and in all complexes an additional nucleobase–metal‐ion interaction occurs. Based on 1H NMR line‐broadening measurements and structural considerations it is concluded that in Cu(3‐deaza‐PMEA) the interaction occurs with N7 whereas in Cu(7‐deaza‐PMEA), Cu(1‐deaza‐PMEA), and Cu(PMEA) it occurs with N3. The proof of a metal ion–N3 interaction is important (and also of relevance regarding DNA) because so far this interaction has received little attention. In all Cu(PA) systems three major isomeric species are in equilibrium; for example, 17(∓3)% of Cu(PMEA) exists as an isomer with a sole Cu2+–phosphonate coordination, 34(∓10)% as Cu(PMEA)cl/O, and in 49(∓10)% the Cu2+ is bound to the phosphonate group, the ether O, and N3. In contrast, 54(∓8)% of Cu(5′‐AMP) occurs as an isomer with sole Cu2+–phosphate coordination and 46(∓8)% as a macrochelate involving N7 too. For the first time a three‐isomer problem has been solved in full detail. The Cu2+ complexes of the N 1, N 3 and N 7 deaza derivatives of the adenine nucleotide analogue PMEA were studied by potentiometric pH titrations (stability constants) and 1H NMR line‐broadening measurements; it was found that Cu2+ interacts with PMEA2‐ through the ‐PO2‐3 group, the ether O, and N 3 of the adenine residue. Consequently, the coordinating properties of PMEA2‐ differ significantly from those of the parent nucleotide 5′‐AMP2‐, which binds metal ions at the ph