Acid-base and metal-ion-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 solution.
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 degrees 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 of previously determined straight-line plots of log K(M(R-PO3))M versus pK(H(R-PO3))H for simple phosph(on)ate ligands, R-PO3(2-), where R represents a residue that does not affect metal-ion binding, proves that the M(PEEA) complexes of Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ as well as the M(PEE) complexes of Co2+, Cu2+, and Zn2+ have larger stabilities than 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 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 (-CH2-O-CH2CH2-PO3(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 PO3(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 M2+ 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.
Department of Chemistry, Inorganic Chemistry, University of Basel, Spitalstrasse 51, CH-4056 Basel, Switzerland.
Alfonso
A
Fernández-Botello
Rolf
R
Griesser
Antonín
A
Holý
Virtudes
V
Moreno
Helmut
H
Sigel
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000998:Antiviral Agents / Q000737:chemistry; D001665:Binding Sites; D002412:Cations; D002614:Chelating Agents / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D007700:Kinetics; D008024:Ligands; D008670:Metals / Q000737:chemistry* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry*; D063065:Organophosphonates / Q000737:chemistry; D011522:Protons
C120290:9-(2-(phosphonomethoxy)ethyl)adenine diphosphate; D000998:Antiviral Agents; D002412:Cations; D002614:Chelating Agents; D008024:Ligands; D008670:Metals; D009942:Organometallic Compounds; D063065:Organophosphonates; D011522:Protons; D000225:Adenine