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

Abstract

Abstract The stability constants of the 1:1 complexes formed between Cu 2+ and the anions of the N 1, N 3, and N 7 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 °C; I = 0.1 M, NaNO 3 ) and compared with previous results for 9‐[2‐(phosphonomethoxy)ethyl]adenine (PMEA 2‐ ) and (phosphonomethoxy)ethane (PME 2‐ ). A microconstant scheme reveals that in Cu(H;PA) + Cu 2+ 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 K Cu Cu(R–PO 3 ) versus p K H H(R–PO 3 ) for simple phosph(on)ate ligands show that all the Cu(PA) complexes, including those with PMEA 2‐ and PME 2‐ , are more stable than expected simply from the basicity of the ‐PO 2‐ group; to some extent five‐membered chelates (Cu(PA) cl/O ) involving the ether oxygen of the ‐CH 2 –O–CH 2 –PO 2‐ 3 chain are formed, and in all complexes an additional nucleobase–metal‐ion interaction occurs. Based on 1 H 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 Cu 2+ –phosphonate coordination, 34(∓10)% as Cu(PMEA) cl/O , and in 49(∓10)% the Cu 2+ 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 Cu 2+ –phosphate coordination and 46(∓8)% as a macrochelate involving N7 too.