Intramolecular π-stacks in mixed-ligand copper(II) complexes formed by heteroaromatic amines and antivirally active acyclic nucleotide analogs carrying a hydroxy-2-(phosphonomethoxy)propyl residue‡

Abstract

Acyclic nucleoside phosphonates (ANPs) are of medical relevance and deserve detailed chemical characterization. We focus here on 1-[2-(phosphonomethoxy)ethyl]cytosine (PMEC), (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC), 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), and (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) and include for comparison the nucleobase-free (phosphonomethoxy)ethane (PME) and (R)-hydroxy-2-(phosphonomethoxy)propane (HPMP). The acidity constants of H3(ANP)+ and H2(NP) (NP2– = nucleoside phosph(on)ate derivative) are needed to understand the properties of the ternary neutral Cu(Arm)(ANP/NP) [Arm = 2,2′-bipyridine (Bpy) or 1,10-phenanthroline (Phen)] and the monoprotonated Cu(Arm)(H;ANP)+ complexes. The Cu(Arm)(ANP) species are considerably more stable than the corresponding Cu(Arm)(R-PO3), where R- represents a phosph(on)ate ligand with a non-coordinating group R. The observed stability enhancements are due to intramolecular stack formation (st) between the aromatic rings of Arm and the nucleobase residues and also to the formation of five-membered chelates involving the ether oxygen of the –CH(R)–O–CH2– residue (cl/O) (R = H or CH2–OH). In intramolecular equilibria, three structurally different Cu(Arm)(ANP) isomers occur; for example, of Cu(Phen)(HPMPA) about 5% exist as an open (op) Cu(Phen)(HPMPA)op isomer, 17% as Cu(Phen)(HPMPA)cl/O, and 78% as Cu(Phen)(HPMPA)st. In Cu(Arm)(ANP) the stacking tendency decreases in the order PMEA2– > HPMPA2– > PMEC2– > HPMPC2–. In monoprotonated Cu(Arm)(H;ANP)+ both H+ and Cu(Arm)2+ are at undergoing similar intramolecular equilibria as indicated above.