Journal
CANADIAN JOURNAL OF CHEMISTRY
Volume 92, Issue 8, Pages 771-780Publisher
CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
DOI: 10.1139/cjc-2014-0041
Keywords
acyclic nucleoside phosphonates; antivirals; intramolecular equilibria; metal-ion complexes; nucleotide analogues; stability constants
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Funding
- Department of Chemistry of the University of Basel
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The acidity constants of protonated 9-[2-(phosphonomethoxy) ethyl]-2-amino-6-dimethylaminopurine (H-3(PME2A6DMAP)(+)) are considered, and the stability constants of the M(H;PME2A6DMAP)(+) and M(PME2A6DMAP) complexes (M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, or Cd2+) were measured by potentiometric pH titrations in aqueous solution (25 degrees C; I = 0.1 mol/L, NaNO3). In the M(H;PME2A6DMAP)(+) species, H+ and M2+ (mainly outersphere) are at the phosphonate group; this is relevant for phosphoryl-diester bridges in nucleic acids because, in the present system, there is no indication for a M2+-purine binding. This contrasts, for example, with the complexes formed by 9-[2-(phosphonomethoxy) ethyl] adenine, M(H;PMEA)(+), where M2+ is mainly situated at the adenine residue. Application of log K-M(R-PO3)(M) vs center dot pK(H(R-PO3))(H) plots for simple phosph(on) ate ligands, R-PO32- (R being a residue that does not affect M2+ binding), proves that all M(PME2A6DMAP) complexes have larger stabilities than what would be expected for a M2+-phosphonate coordination. Comparisons with M(PME-R) complexes, where R is a noncoordinating residue of the (phosphonomethoxy) ethane chain, allow one to conclude that the increased stability is due to the formation of five-membered chelates involving the ether-oxygen of the -CH2-O-CH2-PO32- residue: the percentages of formation of these M(PME2A6DMAP)(cl/O) chelates, which occur in intramolecular equilibria, vary between 20% (Sr2+, Ba2+) and 50% (Zn2+, Cd2+), up to a maximum of 67% (Cu2+). Any M2+ interaction with N3 or N7 of the purine moiety, as in the parent M(PMEA) complexes, is suppressed by the (C2)NH2 and (C6)N(CH3)(2) substituents. This observation, together with the previously determined stacking properties, offers an explanation why PME2A6DMAP(2-) has remarkable therapeutic effects.
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