Collect. Czech. Chem. Commun. 1999, 64, 613-632

Metal Ion-Binding Properties of the Nucleotide Analogue 1-[2-(Phosphonomethoxy)ethyl]cytosine (PMEC) in Aqueous Solution

Claudia A. Blindauera, Antonín Holýb and Helmut Sigela,*

a Institute of Inorganic Chemistry, University of Basel, Spitalstrasse 51, CH-4056 Basel, Switzerland
b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, CZ-16610 Prague 6, Czech Republic


The acidity constants of the twofold protonated nucleotide analogue 1-[2-(phosphonomethoxy)ethyl]cytosine, H2(PMEC)±, as well as the stability constants of the M(H;PMEC)+ and M(PMEC) complexes with the metal ions M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ have been determined by potentiometric pH titrations in aqueous solution at I = 0.1 M (NaNO3) and 25 °C. Comparison with previous results for the nucleobase-free compound (phosphonomethoxy)ethane, PME, and the parent nucleotides cytidine 5'-monophosphate (CMP2-) and 2'-deoxycytidine 5'-monophosphate (dCMP2-) shows that the metal ion-binding properties of PMEC2- resemble closely those of PME2-: This means, the primary binding site is the phosphonate group and with all of the metal ions studied, 5-membered chelates involving the ether oxygen of the -CH2-O-CH2-PO32- chain are formed. The position of the isomeric equilibria between these chelates and the "open" complexes, -PO32-/M2+ is calculated; the degree of formation of the chelates is identical within the error limits for the M(PME) and M(PMEC) systems. Hence, like in M(CMP) and M(dCMP) no interaction occurs with the cytosine residue in the M(PMEC) complexes. However, the monoprotonated M(H;PMEC)+ as well as the M(H;CMP)+ and M(dCMP)+ species carry the metal ion predominantly at the nucleobase, while the proton is at the phosph(on)ate group. The coordinating properties of PMEC2- and CMP2- or dCMP2- differ thus only with respect to the possible formation of the 5-membered chelates involving the ether oxygen in M(PMEC) species, a possibility which does not exist in the complexes of the parent nucleotides. Possible reasons why PMEC is devoid of a significant antiviral activity are shortly discussed.

Keywords: Acidity constants; (S)-1-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine; Metal ion complexes; Phosphonate complexes; 9-[2-(Phosphonomethoxy)ethyl]adenine; Stability constants; Nucleotides; Phosphates; Phosphonates; Chelates; Acyclic nucleotide analogues.