Metal Ion-Binding Properties of (S)-1-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, Cidofovir). A Nucleotide Analogue with Activity Against DNA Viruses

The acyclic nucleoside phosphonate ( S )-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC; Cidofovir) has been approved for clinical use in antiviral therapy. We determined the acidity constants of H 2 (HPMPC) ± , as well as that of the nucleobase-free (hydroxy-2-(phosphonomethoxy)propane (H(HPMP) − ) ( I = 0.1 M, NaNO 3 ; 25 °C). Given that in vivo nucleotides and their analogues participate in reactions typically as metal ion (M 2+ ) complexes, the stability constants of the M(H;HPMPC) + , M(HPMPC), and M(HPMP) complexes with M 2+ = Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Mn 2+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ , and Cd 2+ were measured. Comparisons between results for HPMP 2− and previous data for PME 2− ( CH3CH2OCH2PO32-"> ; phosphonomethoxyethane) revealed the hydroxyl-group effect. The hydroxyl group stabilizes only complexes with the heavier alkaline earth metal ions (Ca 2+ , Sr 2+ , Ba 2+ ). For all other complexes, the enhanced stability can solely be explained by the formation of 5-membered chelates involving the ether oxygen; these occur in equilibrium with simple 'open' phosphonate-M 2+ species. The stability of the M(HPMPC) complexes is also higher than expected for a phosphonate-only coordination, indicating that chelates are formed, but comparison with the HPMP 2− data shows that the cytosine base does not affect complex stability. Similar observations were made previously with related cytosine derivatives. The stability data for the monoprotonated M(H;HPMPC) + complexes suggest that these carry H + predominantly on the phosphonate group, and M 2+ on the nucleobase.