Ternary complexes in solution (part 55¹) with phosphonates as ligands. Various intramolecular equilibria in mixed-ligand complexes containing the antiviral 9-(2-phosphonomethoxyethyl)adenine, an adenosine monophosphate analogue

Abstract

The stability constants of the mixed-ligand complexes formed between Cu(arm)2+, where arm = 2.2'bipyridyl (bipy) or 1,lO-phenanthroline (phen), and the dianions of phosphonomethoxyethane (PME2-) or 9-(2-phosphonomethoxyethyl)adenine (PM EAZ-) were determined by potentiometric pH titration in aqueous solution at 25 "C and / = 0.1 mol dm-, (NaNO,). The stability of the binary (arm) (PMEA)2-stacks was estimated and the experimental conditions for the titrations were carefully selected such that selfassociation of the adenine derivative PMEA and of its complexes was negligible, i.e. it was made certain that the properties of the monomeric Cu(arm) (PMEA) complexes were studied. The ternary Cu(arm) (PMEA) complexes are considerably more stable than the corresponding Cu(arm) (R-PO,) complexes, where R-P0,2-represents a phosphonate (or a phosphate monoester) with a group R that is unable to participate in any kind of interaction within the complexes as, for example, methylphosphonate or ethylphosphonate. This increased stability is attributed to intramolecular stack formation in the Cu(arm)( PMEA) complexes and also to the formation of five-membered chelates involving the ether oxygen present in the -O-CH2-P0,Z-residue of PMEA*-. The latter interaction is separately quantified by studying the ternary Cu(arm) (PME) complexes which can form the five-membered chelates but where no intramolecular ligand-ligand stacking is possible. Application of these results allows a quantitative analysis of the intramolecular equilibria involving three structurally different Cu(arm) (PMEA) species, e.g. of the Cu (bipy) (PM EA) system about 3% exist with the metal ion solely co-ordinated to the phosphonate group, 10% as a five-membered chelate involving the -O-CH2-P0,Z-residue of PMEA2-, and 87% with an intramolecular stack between the adenine moiety of PMEA2-and the aromatic rings of bipy. In addition, the Cu(arm)(PMEA) complexes may be protonated leading to Cu(arm)(H-PMEA) species for which it is concluded that the proton is mainly located at the phosphonate group. However, of this species t w o isomers still coexist, one where Cu(arm)zf forms a stack with the adenine residue of H(PMEA)-and another one where Cu(arm)2+ co-ordinates in an adenosine-type fashion to the nucleic base moiety of H (PM EA) -; the percentages of the formation degree of these isomeric species have been estimated. Finally, the properties of adenosine 5'-monophosphate (AMPZ-) and of its PMEA2-analogue are compared in their ternary Cu(arm) (AMP) and Cu(arm) (PMEA) systems. The co-ordinating properties of the ether oxygen, which are crucial for the antiviral properties of PMEA, are discussed. * 27.5 k 11.1 36 1 1 25.1 k 7.8 33 1 1 29.7 k 5.4 38 11 31.0 k 9.5 42 15 26.8 k 7.4 38 14 13.6 +_ 3.9 16 14 37 ? 9' 16 f 5' The error limits correspond to twice the standard deviation (20). * Stability constants corrected for the self-association of arm (cf. ref. 14).' These values and their error limits are estimates based on the other entries of the table.

Extent of intramolecular π stacks in aqueous solution in mixed-ligand copper(II) complexes formed by heteroaromatic amines and the anticancer and antivirally active 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG). A comparison with related acyclic nucleotide analogues

“…The constants for Equilibria (5a), (6a), and (7a) are listed in columns 3, 4, and 5 of Table 2 for the complexes of PMEG, respectively, together with some related data for other PE ligands [2,57,66,70]. The stability constants for the binary Cu(H;PMEG) + and Cu(PMEG) complexes will be mainly discussed elsewhere in a different context.…”

“…Indeed, statistical considerations predict for Δ log K Cu a value of about -0.5 for the coordination of a monodentate ligand to Cu(Arm) 2+ [75]. However, for simple phosph(on)ates Δ log K Cu equals about 0.03 [70,76] Comparing the above with the results listed in column 6 of Table 2 shows that Δ log K Cu has a positive sign and is also larger than expected for all the ternary complexes, indicating that Equilibrium (9a) is shifted towards its right side. One may add that in the Cu(Arm)(PME) complexes, Δ log K Cu being about 0.15 (Table 2, entry 1), the ether oxygen atom (see Fig.…”

“…An alternative way to evaluate the stability of ternary complexes, independently of the properties of the binary ones, rests in the present case for Cu(Arm)(R-PO 3 ) complexes on the previously established [70,79] straight-line correlations [80] for log K Cu(Arm)(R-PO 3 )…”

“…participates in metal ion binding in about 75% of the species [70], that is, PME 2-acts to a large extent as a bidentate ligand (see Section 3.7 and Ref. [1]).…”

“…In these plots R-PO 3 2! represents phosphate monoesters or phosphonate ligands, in which the residue R is unable to interact with Cu(Arm) 2+ [70]. The corresponding straight-line parameters for Cu(R-PO 3 ) (Eq.…”