| Abstract
| - PEEA2-, a nucleotide analogue and close relative of the antivirally active PMEA2-, is a very versatile ligand. Depending on the metal ion involved, it is able to form up to four isomers in aqueous solution, the formation degrees of which are quantified. Furthermore, an explanation is given why PMEA is a nucleotide analogue with excellent antiviral properties and PEEA is not.
- The acidity constants of 3-fold protonated 9-[2-(2-phosphonoethoxy)ethyl]adenine, H3(PEEA)+, and of 2-fold protonated(2-phosphonoethoxy)ethane, H2(PEE), and the stability constants of the M(H;PEEA)+, M(PEEA), and M(PEE)complexes with M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, or Cd2+ have been determined(potentiometric pH titrations; aqueous solution; 25 °C; I = 0.1 M, NaNO3). 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 ofpreviously determined straight-line plots of logversusfor simple phosph(on)ate ligands,R−PO32-, where R represents a residue that does not affect metal-ion binding, proves that the M(PEEA) complexesof Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ as well as the M(PEE) complexes of Co2+, Cu2+, and Zn2+ have larger stabilitiesthan is expected for a sole phosphonate coordination of M2+. For the M2+ complexes without an enhanced stability(e.g., Mg2+ or Mn2+), it is concluded that M2+ binds in a monodentate fashion to the phosphonate group of the twoligands. 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 theether-oxygen atom of the aliphatic residue (−CH2−O−CH2CH2−PO32-) of the ligands with formation degrees ofabout 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% isdue to the “open” isomer Zn(PEEA)op in which the metal ion binds only to the PO32- group. (iv) Most remarkableis Cu(PEEA) because a fourth isomer, Cu(PEEA)cl/O/N3, is formed that contains a six-membered ring involving theether oxygen next to the phosphonate group and also a seven-membered ring involving N3 of the adenine residuewith a very significant formation degree of about 50%. Hence, PEEA2- is a truly ambivalent ligand, its propertiesbeing strongly dependent on the kind of metal ion involved. Comparisons with M2+ complexes formed by thedianions of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and related ligands reveal that five-membered chelatesinvolving an ether-oxygen atom are considerably more stable than the corresponding six-membered ones. Thisobservation offers an explanation of why PMEA is a nucleotide analogue with excellent antiviral properties andPEEA is not.
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