Gómez-Coca, Raquel B., Blindauer, Claudia A., Sigel, Astrid, Operschall, Bert P., Holý, Antonín and Sigel, Helmut. (2012) Extent of intramolecular π-stacks in aqueous solution in mixed-ligand copper(II) complexes formed by heteroaromatic amines and several 2-aminopurine derivatives of the antivirally active nucleotide analog 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA). Chemistry & Biodiversity, Vol.9 (No.9). pp. 2008-2034. ISSN 1612-1872

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Abstract

The acidity constants of twofold protonated, antivirally active, acyclic nucleoside phosphonates (ANPs), H2(PE)±, where PE2−=9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2−), 2-amino-9-[2-(phosphonomethoxy)ethyl]purine (PME2AP2−), 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP2−), or 2-amino-6-(dimethylamino)-9-[2-(phosphonomethoxy)ethyl]purine (PME(2A6DMAP)2−), as well as the stability constants of the corresponding ternary Cu(Arm)(H;PE)+ and Cu(Arm)(PE) complexes, where Arm=2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen), are compared. The constants for the systems containing PE2−=PMEDAP2− and PME(2A6DMAP)2− have been determined now by potentiometric pH titrations in aqueous solution at I=0.1m (NaNO3) and 25°; the corresponding results for the other ANPs were taken from our earlier work. The basicity of the terminal phosphonate group is very similar for all the ANP2− species, whereas the addition of a second amino substituent at the pyrimidine ring of the purine moiety significantly increases the basicity of the N(1) site. Detailed stability-constant comparisons reveal that, in the monoprotonated ternary Cu(Arm)(H;PE)+ complexes, the proton is at the phosphonate group, that the ether O-atom of the CH2OCH2P(O)(OH) residue participates, next to the P(O)(OH) group, to some extent in Cu(Arm)2+ coordination, and that ππ stacking between the aromatic rings of Cu(Arm)2+ and the purine moiety is rather important, especially for the H⋅PMEDAP− and H⋅PME(2A6DMAP)− ligands. There are indications that ternary Cu(Arm)2+-bridged stacks as well as unbridged (binary) stacks are formed. The ternary Cu(Arm)(PE) complexes are considerably more stable than the corresponding Cu(Arm)(RPO3) species, where RPO represents a phosph(on)ate ligand with a group R that is unable to participate in any kind of intramolecular interaction within the complexes. The observed stability enhancements are mainly attributed to intramolecular-stack formation in the Cu(Arm)(PE) complexes and also, to a smaller extent, to the formation of five-membered chelates involving the ether O-atom present in the CH2OCH2PO residue of the PE2− species. The quantitative analysis of the intramolecular equilibria involving three structurally different Cu(Arm)(PE) isomers shows that, e.g., ca. 1.5% of the Cu(phen)(PMEDAP) system exist with Cu(phen)2+ solely coordinated to the phosphonate group, 4.5% as a five-membered chelate involving the ether O-atom of the CH2OCH2PO residue, and 94% with an intramolecular ππ stack between the purine moiety of PMEDAP2− and the aromatic rings of phen. Comparison of the various formation degrees of the species formed reveals that, in the Cu(phen)(PE) complexes, intramolecular-stack formation is more pronounced than in the Cu(bpy)(PE) species. Within a given Cu(Arm)2+ series the stacking intensity increases in the order PME2AP2−<PMEA2−<PMEDAP2−<PME(2A6DMAP)2−. One could speculate that the reduced stacking intensity of PME2AP2−, together with a different H-bonding pattern, could well lead to a different orientation of the 2-aminopurine moiety (compared to the adenine residue) in the active site of nucleic acid polymerases and thus be responsible for the reduced antiviral activity of PME2AP compared with that of PMEA and the other ANPs containing a 6-amino substituent.

Item Type:	Journal Article
Divisions:	Faculty of Science > Chemistry
Journal or Publication Title:	Chemistry & Biodiversity
Publisher:	Wiley - V. C. H. Verlag
ISSN:	1612-1872
Date:	September 2012
Volume:	Vol.9
Number:	No.9
Page Range:	pp. 2008-2034
Identification Number:	10.1002/cbdv.201200022
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/50262

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