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.

The stability constants of the I:1 complexes formed between hlg", Ca2+, Sr", BaZ+, hIn'+, Co2+, NiZ+, Cu2+. Zn2+ or Cdz+ and orotidinate S'-monophosphate (OhlP'-) were determined by potentiometric pH titrations in aqueous solution (I = 0.1 M, NaNO,; 2S'C). In addition to the stability constants of these M(0hlP)-complexes, for several cases also the corresponding acidity constants for the release of the proton from the H(N-3) site were calculated; i.e., the formation of M(0hlP-H)'-complexes was quantified. On the basis of recent measurements for simple phosphate monoesters [R-hlP2-; R is a noncoordinating residue; S.S. hlassoud and H. Sigel, biorg. Clieni., 27, 1447-1453 (1988)], evidence is provided that the somewhat increased stability of all the mentioned hl(0MP)-complexes is mainly the result of a charge effect of the carboxylate group (in position 6 of OhlP'-) and riot of a direct participation in complex formation; i.e., there are no indications for the formation of significant amounts of macrochelates involving the phosphate and the carboxylate groups. This is different for the M(0MP-H)'-complexes of Co2+, NiZC and Cd2+: in these cases significant amounts of macrochelates form; i.e., the metal ion is not only coordinated to the phosphate group but also (in part) to the ionized -(N-3) site, which is placed in the neighbourhood of the phosphate residue in the dominating sjn conformation of this nucleotide. For the metal ions hlg2+, Ca2+, Sr2+, BaZ+ and hln2+, which have in general a rather low afinity for N binding sites, no evidence for the formation of macrochelates is detected. In addition, the stability constants of the ternary Cu(Arm)(OMP)-complexes, where Arm = 2,T-bipyridyl or 1,lOphenanthroline, were determined by potentiometric pH titrations. Evaluation of the stability data shows that an equilibrium betweeen an 'open' isomer and a Cu(Arm)(Oh$P)-species with an intramolecular stack exists; the formation degree of these aromatic ring stacks reaches about 40 percent. Overall it is quite evident that OhlP3-is a versatile Iigand with remarkable properties which may be utilized by nature in recognition reactions during the intricate metabolic processes in which this nucleotide is involved.

The acidity constants of H(R-MP)", where R-MP1 2" = dihydroxyacetone phosphate (DHAP2") and glycerol 1-phosphate (G1P2"), and the stability constants of the binary M(R-MP) complexes (M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+) were determined by potentiometric pH titrations in aqueous solution (/ = 0.1 M, NaN03; 25 °C). The stability of the ternary Cu(Arm)(R-MP) complexes (Arm = 2,2'-bipyridyl or 1,10-phenanthroline) were also measured. On the basis of recent results for simple phosphate monoesters, R-MP2", where R is a strictly noncoordinating residue (Massoud, S. S.; Sigel, H. Inorg. Chem. 1988Chem. ,27,1447Chem. -1453, it is established that the stability of all the M(DHAP) and M(G1P) complexes is governed by the basicity of the phosphate group of DHAP2" and G1P2". There are no indications in aqueous solution for the participation of the oxygen atom of the carbonyl or hydroxy groups at C-2 of these ligands in complex formation, which would on steric grounds be possible. However, measurements with Cu2+ and DHAP2" or G1P2" in water containing 30 or 50% (v/v) 1,4-dioxane (/ = 0.1 M, NaN03; 25 °C) prove that to some extent seven-membered chelates involving the mentioned oxygen atoms may be formed. This may also be surmised for the other mentioned divalent metal ions under appropriate conditions, because it is well-known that they all can interact with the oxygen of carbonyl or hydroxy groups, especially when the solvent has poorer solvating properties than water. This condition exists in active-site cavities of enzymes; therefore, the indicated type of metal ion interaction could play a role in certain metabolic processes involving DHAP (or GAP; see below) and G1P. It is further concluded that the proton and metal ion affinities of glyceraldehyde 3-phosphate (GAP2") correspond in a first approximation to those of G1P2" because both ligands contain the same structural unit, i.e., -CH(0H)CH20P032', which is responsible for the proton and metal ion binding properties, as shown now for G1P2". This conclusion regarding GAP is meaningful because this ligand may hardly be studied directly due to its conversion into DHAP.

Coordination of two monoprotonated 2'-deoxyguanosine 5'-monophosphate species, H(dGMP)−, via N7 to cis-(NH2)2Pt2+ gives the complex cis-(NH2)2Pt(H·dGMP)2 which is a four-protonic acid. The corresponding acidity constants were measured by potentiometric pH titrations (25℃; I = 0.1 M, NaNO3). The first two protons are released from the two -P(O)2(OH)− groups (PKa/1= 5.57; PKa/2 = 6.29) and the next two protons are from the H(N1) sites of the guanine residues (PKa/3 = 8.73; PKa/4 = 9.48). The micro acidity constants of the various sites are also evaluated. Comparison of these data with those determined for the three-protonic H2(dGMP)± (PKa/1 = 2.69 for the H+(N7) site; PKa/2 = 6.29 for -P(O)2(OH)− ;PKa/3 = 9.56 for H(N1)) shows that on average the N-7-coordinated Pt2+ acidifies the phosphate protons by Δ pKa = 0.36 and the H(N1) sites by Δ pKa = 0.46. These results are further compared with those obtained previously for cis-(NH2)2Pt(L)2, where L = 9-ethylguanine or monoprotonated 2'-deoxycytidine 5'-monophosphate. Conclusions regarding platinated DNA are also presented.

The pyrophosphoric-acid-analogue phosphonoformic acid (pfa) and the amino-acid-analogue (aminomethy1)phosphonic acid (ampa) both form, in the deprotonated state, i.e., as -0OC-PO;-and H2N-CH2-PO:-, respectively, five-membered chelate rings with metal ions. pfa inhibits both phosphate transport and virus replication, while ainpa is a metabolic product of the common herbicide glyphosate ( = N-(phosphonomethy1)glycine). The acidity constants of H,pfa-and H2ampa* as well as the stability constants of the [M(Hpfa)], [M(pfa)]-, [M(Hampa)]+, and fM(ampa)] complexes, where M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, C~(2,2'-bipyridyl)*~, Cu( I , 10-phenantbroline)2+, Zn2+, or Cd2', have been determined by potentiometric pH titrations in aqueous solution at 25" and I = 0 . l~ (NaNO,). The structures of isomeric complexes and the connected intramolecular equilibria are deduced and evaluated based on the equilibrium constants measured and those calculated via the pK, values of the above mentioned ligands and previously established log K 1's. pK, straight-line plots ( H . Sigel et ul., Helv. Chim. Acra 1992, 75, 2634) for a simple phosphonate-M2+ coordination. pfa forms stronger complexes than ampa with all the above mentioned metal ions, with the single exception of "&(ampa)] which is slightly more stable than [Cu(pfa)]-. In neutral solutions, more precisely at pH of ca. 6, pfa complexes of alkaline-earth-metal ions retain one phosphonate-bound proton, [M(Hpfa)], whilc those of the transition-metal ions chelate with the trianionic ligand, pfa'? In accord with increasing ligand-basicity, the stability-constant order for all metal-ion complexes is oxalate < pfa < pyrophosphate but, owing to proton competition in pyrophosphate, in neutral solutions metal-ion complexation of pfa3-competes with P20$-. With ampa alkaline-earth-metal ions interact only with the phosphonate group of even the dianionic ligand (though Mg" appears to form a low fraction of a [Mg(ampa)] chelate) while transition-metal ions form chelates which are comparable in stability to those of glycinate.