Metal-ion binding properties of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, Cidofovir). A nucleotide analogue with activity against DNA viruses

Metal Ion‐Coordinating Properties in Aqueous Solutions of the Antivirally Active Nucleotide Analogue (S)‐9‐[3‐Hydroxy‐2‐(phosphonomethoxy)propyl]adenine (HPMPA) – Quantification of Complex Isomeric Equilibria

“…The evaluation of potentiometric pH titration data only allows the determination of the stability constants of the M(H;HPMPA) + complexes. Further information is required to detect the binding sites of the proton and the metal ion , , ,…”

“…The points due to the equilibrium constants for the M 2+ /HPMPA (●) systems are based on the values listed in Table and Table ; those for the M 2+ /PMEA systems (⊗) are from ref ,. for the M 2+ /HPMP systems (◆) from ref ,. and those for the M 2+ /PME systems (▵) from ref …”

“…For the error limits see footnote [b] of Table . The values in the second column are from column 4 in Table , those in the 3rd and 5th column are from ref and refs, , respectively. In addition, for example, log Δ HPMPA should correctly be written as log Δ M/HPMPA [see also Equation (17)]; however, for reasons of clarity "M" is deleted in all expressions above.…”

“…Since the substrates for kinases and nucleic acid polymerases are actually metal complexes of the respective nucleoside mono‐ or triphosphates, it is conceivable that the metal ion‐binding properties of ANPs may also play a role in the activity of these compounds, motivating a research programme dedicated to understanding stability and structures of ANP metal complexes . The ether oxygen has been shown to be essential for biological activity, but also to play a pivotal role in metal ion binding of these compounds: It permits the formation of five‐membered chelates , . Finally, in terms of biological activity, the position of the hydroxyl group matters, as "iso‐HPMPA", ( S )‐9‐[2‐hydroxy‐2‐(phosphonomethoxy)propyl]adenine), is inactive …”

“…The binary H(HPMPA) – and HPMPA 2– systems with Ca 2+ , Cu 2+ , and Zn 2+ were investigated previously in a preliminary study and these results were confirmed now . With comparative data for the nucleobase‐free parent compound HPMP now available, it has become possible to comprehensively evaluate the stability constants of the binary M(H;HPMPA) + and M(HPMPA) complexes, formed with M 2+ = Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Mn 2+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ , and Cd 2+ , and to assess their structures in solution revealing in part up to three different isomeric species, including N3 as a binding site.…”