Complex formation of the antiviral 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and of its N1, N3, and N7 deaza derivatives with copper(II) in aqueous solution

The stability constants of the 1:1 complexes formed between Cu2+ and the anions of the N1, N3, and N7 deaza derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PA(2-)), Cu(H;PA)(+) and Cu(PA), were determined by potentiometric pH titration in aqueous solution (25 degrees C: I = 0.1 M, NaNO3) and compared with previous results for 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA(2-)) 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 KCu(R-PO3)(Cu) versus pK(H(R-PO3))(H) for simple phosph(on)ate ligands show that all the Cu(PA) complexes, including those with PMEA(2-) and PME2-, are more stable than expected simply from the basicity of the -PO32- group; to some extent five-membered chelates (Cu(PA(cl/O)) involving the ether oxygen of the -CH2-O-CH2-PO32- chain are formed, and in all complexes an additional nucleobase-metal-ion interaction occurs. Based on H-1 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.