Acid-Base and Metal-lon-Binding Properties of 9-[2-(2-Phosphonoethoxy)ethyl]adenine (PEEA),a Relative of the Antiviral Nucleotide Analogue 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA).An Exercise on the Quantification of Isomeric Complex Equilibria in

摘要

The acidity constants of 3-fold protonated 9-[2-(2-phosphonoethoxy)ethyl]adenine,H_3(PEEA)~+,and of 2-fold protonated (2-phosphonoethoxy)ethane,H_2(PEE),and the stability constants of the M(H;PEEA)~+,M(PEEA),and M(PEE) complexes with M~(2+)=Mg~(2+),Ca~(2+),Sr~(2+),Ba~(2+),Mn~(2+),Co~(2+),Ni~(2+),Cu~(2+),Zn~(2+),or Cd~(2+) have been determined (potentiometric pH titrations;aqueous solution;25degC;I=0.1 M,NaNO_3).It is concluded that in the M(H;PEEA)~+ species,the proton is at the phosphonate group and the metal ion at the adenine residue.The application of previously determined straight-line plots of log K_(M(R-PO_3)~M versus pK_(H(R-PO_3)~R for simple phosph(on)ate ligands,R-PO_3~(2-),where R represents a residue that does not affect metal-ion binding,proves that the M(PEEA) complexes of Co~(2+),Ni~(2+),Cu~(2+),Zn~(2+),and Cd~(2+) as well as the M(PEE) complexes of Co~(2+),Cu~(2+),and Zn~(2+) have larger stabilities than is expected for a sole phosphonate coordination of M~(2+).For the M~(2+) complexes without an enhanced stability (e.g.,Mg~(2+) or Mn~(2+)),it is concluded that M~(2+) binds in a monodentate fashion to the phosphonate group of the two ligands.Combination of all of the results allows the following conclusions:(i) The increased stability of the Co(PEE),Cu(PEE),Zn(PEE),and Co(PEEA) complexes is due to the formation of six-membered chelates involving the ether-oxygen atom of the aliphatic residue (-CH_2-0-CH_2CH_2-P0_3~(2-)) of the ligands with formation degrees of about 15-30%.(ii) Cd(PEEA) forms a macrochelate with N7 of the adenine residue (formation degree about 30%);Ni(PEEA) has similar properties,(iii) With Zn(PEEA),both mentioned types of chelates are observed,that is,Zn(PEEA_(Cl/O) and Zn(PEEA)_(cl/N7),with formation degrees of about 13 and 41%,respectively;the remaining 46% is due to the "open" isomer Zn(PEEA)_(op) in which the metal ion binds only to the P0_3~(2-) group,(iv) Most remarkable is Cu(PEEA) because a fourth isomer,Cu(PEEA)_(cl/O/N3),is formed that contains a six-membered ring involving the ether oxygen next to the phosphonate group and also a seven-membered ring involving N3 of the adenine residue with a very significant formation degree of about 50%.Hence,PEEA~(2-) is a truly ambivalent ligand,its properties being strongly dependent on the kind of metal ion involved.Comparisons with M~(2+) complexes formed by the dianions of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and related ligands reveal that five-membered chelates involving an ether-oxygen atom are considerably more stable than the corresponding six-membered ones.This observation offers an explanation of why PMEA is a nucleotide analogue with excellent antiviral properties and PEEA is not.