Solution properties of metal ion complexes formed with the antiviral and cytostatic nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]-2-amino-6-dimethylaminopurine (PME2A6DMAP)

0435258 - ÚOCHB 2015 RIV CA eng J - Článek v odborném periodiku
Gómez-Coca, R. B. - Sigel, A. - Operschall, B. P. - Holý, Antonín - Sigel, H.
Solution properties of metal ion complexes formed with the antiviral and cytostatic nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]-2-amino-6-dimethylaminopurine (PME2A6DMAP).
Canadian Journal of Chemistry. Roč. 92, č. 8 (2014), s. 771-780. ISSN 0008-4042. E-ISSN 1480-3291
Institucionální podpora: RVO:61388963
Klíčová slova: acyclic nucleoside phosphonates * antivirals * intramolecular equilibria * metal-ion complexes * nucleotide analogues * stability constants
Kód oboru RIV: CC - Organická chemie
Impakt faktor: 1.061, rok: 2014

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.
Trvalý link: http://hdl.handle.net/11104/0239547