Rolf Griesser

Effects of (N7)-Coordinated Nickel(II), Copper(II), or Platinum(II) on the Acid–Base Properties of Guanine Derivatives and Other Related Purines[≠]

Guanine is an important nucleobase residue in nucleic acids; for example, the anticancer drug cisplatin, cis-[(NH3)2PtCl2], preferably binds to N7 of this site. In this study the effect of (N7)-coordinated Ni2+ (which is expected to correspond to that of Zn2+), Cu2+, and cis-a2Pt2+ or trans-a2Pt2+ (where a = NH3 or CH3NH2) on the acid–base properties of guanine derivatives (see diagram) is quantified. Several related purines are included for comparison. Micro-acidity-constant evaluations are presented and more than 60 acidity constants are listed.

Influence of decreasing solvent polarity (1,4-dioxane/water mixtures) on the stability and structure of complexes formed by copper(II), 2,2′-bipyridine or 1,10-phenanthroline and guanosine 5′-diphosphate: evaluation of isomeric equilibria† ‡

The stability constants of the 1 : 1 complexes formed between Cu(Arm)2+, where Arm = 2,2′-bipyridine or 1,10-phenanthroline, and guanosine 5′-diphosphate (GDP)3− or its monoprotonated form H(GDP)2− were determined by potentiometric pH titrations in water and in water containing 30 or 50% (v/v) 1,4-dioxane (25°C; I = 0.1 M, NaNO3). The stability of the binary Cu(GDP)− complex is enhanced due to macrochelate formation of the diphosphate-coordinated Cu2+ with N7 of the guanine residue as previously shown. In Cu(Arm)(GDP)− the N7 is released from Cu2+ and the stability enhancement of more than one log unit in aqueous solution is clearly attributable to intramolecular stack formation between the aromatic rings of Arm and the guanine moiety. Indeed, stacked isomers occur to more than 90% in equilibrium with open unstacked forms. Surprisingly, the same formation degrees of the stacks are observed for Cu(Arm)(dGMP) complexes, where dGMP2− = 2′-deoxyguanosine 5′-monophosphate, despite the fact that the overall stability of the latter species is by about 2.7 log units lower. In 1,4-dioxane–water mixtures stack formation is drastically reduced, probably due to hydrophobic solvation of the aromatic rings by the ethylene bridges of 1,4-dioxane. The relevance of these results regarding biological systems is indicated. †This study is dedicated to Professor Dr Alfredo Mederos on the occasion of his retirement from the University of La Laguna (Spain) with the very best wishes for all of his future endeavors. ‡This is part 70 of the series Ternary Complexes in Solution; for parts 69 and 68 see 14 and 15, respectively.

Synthesis and acid–base properties of (1H-benzimidazol-2-yl-methyl)phosphonate (Bimp2−). Evidence for intramolecular hydrogen-bond formation in aqueous solution between (N-1)H and the phosphonate group

The synthesis of (1H-benzimidazol-2-yl-methyl)phosphonic acid, H2(Bimp)+/-, is described: 2-chloromethylbenzimidazole was reacted with ethylchloroformate to give 1-carboethoxy-2-chloromethylbenzimidazole which was treated with trimethyl phosphite and after hydrolysis with aqueous HBr H2(Bimp)+/- was obtained. In H2(Bimp)+/- one proton is at the N-3 site and the other at the phosphonate group; both acidity constants were determined in aqueous solution by potentiometric pH titrations (25 degrees C; I = 0.1 M, NaNO3) and this furnished the pKa values of 5.37 +/- 0.02 and 7.41 +/- 0.02, respectively. The acidity constant for the release of the primary proton from the P(O)(OH)2 group of H3(Bimp)+ was estimated: pKa = 1.5 +/- 0.2. Moreover, Bimp2- can be further deprotonated at its neutral (N-1/N-3)H site to give the benzimidazolate residue, but this reaction occurs only in strongly alkaline solution (KOH); application of the H_ scale developed by G. Yagil (J. Phys. Chem., 1967, 71, 1034) together with UV spectrophotometric measurements gave pKa = 14.65 +/- 0.12. Comparisons with acidity constants taken from the literature show that this latter pKa value is far too large and this allows the conclusion that an intramolecular hydrogen bond is formed between the (N-1/N-3)H site and the phosphonate group of Bimp2-; the formation degree of this hydrogen-bonded isomer is estimated to be 98 +/- 2%. The general relevance of this and the other results are shortly discussed and the species distribution for the Bimp system in dependence on pH is provided.

“Hard and soft” behavior of Mn2+, Cu2+, and Zn2+ with respect-to carboxylic acids and α-oxy- or α-thio-substituted carboxylic acids of biochemical significance

Abstract An investigation has been made on the coordination of Mn2+, Cu2+, and Zn2+, by several simple carboxylic acids and certain of α-oxy- and α-thiocarboxylic acids which have biochemical significance. The stability constants of the 1:1 complexes have been measured in water containing 50% dioxane (I = 0.1; t = 25 °). With all three metal ions, the expected correlations between the basicity of the monodentate ligands and the stability of the complexes were found. The following potential bidentate α-oxyor α-thiocarboxylic acids were included in the measurements: Tetrahydrofuran 2-carboxylic acid (XI), hydroxyacetic acid (XII), tetrahydrothiophene 2-carboxylic acid (XIII), and S-carboxymethyl ethyl mercaptan (XIV). The complexes of the carboxylic acids with an oxygen in the α-position, (XI, XII), are more stable with all three metal ions than is expected on the basis of participation of the carboxyl function alone, i.e., chelates are formed. For the carboxylic acids with sulfur in the α-position, (XIII, XIV), such chelation is definite only for the Cu2+ complexes. The values of the Zn2+ and especially the Mn2+ complexes are in the order expected from basicity of the carboxylate groups, i.e., there is no or only a weak coordination of the sulfur atom. NMR spectra of S-carboxymethyl ethyl mercaptan (XIV) with increasing amounts of the paramagnetic ions, Cu2+ and Mn2+, confirm these results: In the case of Cu2+, the sulfur is strongly coordinated and a bidental chelate ligand results, while with Mn2+ the spectra suggest that interaction with sulfur is weak and the simple monodental carboxylate complex probably dominates. These results are discussed with respect to Pearsons “hard-soft” rule and the selection of the coordinating groups in biological complexes, i.e., the question about the “selection rules” which determine the structure and reactivity in such complexes is considered.

Ternary complexes in solution. XIII. Mixed-ligand complexes of copper(II) or zinc(II) with 2,2′-bipyridyl and thioether carboxylates or some of the sulfoxide or sulfone derivatives

Abstract The stability constants of ternary Cu2+ and Zn2+ complexes, each of which contained 2,2′-bipyridyl and a second ligand of carboxymethyl alkyl or aryl sulfide or the sulfoxide or sulfone derivative, were determined by potentiometric titration in 50% aqueous dioxane (I = 0.1, NaClo4; 25°). A comparison of the stability of these ternary complexes with those formed with simple carboxylates indicates that the thioether (or sulfoxide or sulfone) groups participate in complex formation in all the mixed-ligand cases. This is different from the results obtained recently for the binary complexes of Cu2+ and Zn2+ with thioether carboxylates: chelate formation is definite only for the binary complexes with carboxymethyl alkyl sulfides, while with carboxymethyl aryl sulfides, the stability constants are of an order that can be explained by the formation of simple carboxylate complexes alone.

Comparison of the acid–base properties of purine derivatives in aqueous solution. Determination of intrinsic proton affinities of various basic sites

The acidity constants of protonated 7,9-dimethylguanine, 7-methylguanosine, 7,9-dimethylhypoxanthine, 7-methylinosine, 9-methyladenine, 1,9-dimethyladenine, 7,9-dimethyladenine and 1-methyladenosine were determined in aqueous solution at 25 °C and I = 0.1 M (NaNO3). In those instances where pKa > 2 potentiometric pH titrations were used for the determinations; when pKa < 2, UV spectrophotometric and 1H-NMR shift measurements were employed (25 °C). In these latter instances, where I is often larger than 0.1 M, the H0 scale was applied to define the H+ activity of the strong acid (HClO4; HNO3). A combination of the present results with values taken from our earlier work allowed us to quantify the intrinsic acidic properties in aqueous solution of the (N1)H0 or + and (N7)H+ sites via micro acidity constant schemes for seven purine derivatives and to calculate the tautomeric ratios regarding the monoprotonated species, that is N7–N1·H versus H·N7–N1 meaning that in one isomer H+ is at the N1 site and in the other at N7. A plot of the micro acidity constants pkN7–N1H·N7–N1, which quantify the acidity of the (N7)H+ site, versus the macro acidity constants pKa/(N1)H, which largely refer to the release of the proton from the (N1)H unit, results in a straight line for the guanine and hypoxanthine derivatives. This fact allows estimation of the micro acidity constant for any related derivative provided a value for pKa/(N1)H is known. The presented results are also meaningful for nucleic acids because they quantify the acid–base properties of their individual sites.

Ternary Complexes in Solution, XII. Models for Biological Mixed-Ligand Complexes: 2,2′-Bipyridyl-Cu2+-Oligoglycine Systems

The stability constants of the binary Cu2+ complexes of glycine amide, diglycine, diglycine amide, triglycine, and tetraglycine were determined, as were those of the mixed-ligand Cu2+ systems containing 2,2′-bipyridyl and one of the mentioned oligoglycines. The results evidence that all these complexes have the same structure and, therefore, the binding sites of the ligands have to be the terminal amino group and the oxygen of the neighbored amide group. The stability differences between the ternary and the binary complexes are in agreement with this interpretation. It is of interest to note that these ternary complexes are significantly more stable than expected on statistical reasons. With increasing pH, the amide groups in the binary complexes are successively deprotonated. Thus, with tetraglycine finally all three amide protons are displaced, and the amide nitrogens are bound to the square-planar coordination sphere of Cu2+. As in the Cu2+-2,2′-bipyridyl 1 : 1 complex, only two coordination positions are left for the binding of the oligoglycine, in the tenary complexes, only one amide group can be deprotonated. An increase in pH with deprotonation of other amide groups leads to a displacement of 2,2′-bipyridyl, i. e. the simple binary complexes result. No evidence could be observed for the coordination of a deprotonated amide group to an apical position of the coordination sphere of Cu2+. Additionally, while the displacement of the first amide proton in the several binary Cu2+ oligoglycine complexes occurs over a large pH range (4 to 7), the deprotonation in all the mixed-ligand complexes takes place at pH approximately 8.

Comparison of the Surprising Metal-Ion-Binding Properties of 5-and 6-Uracilmethylphosphonate (5Umpa2-and 6Umpa2-) in Aqueous Solution and Crystal Structures of the Dimethyl and Di(isopropyl) Esters of H2(6Umpa)

5- and 6-Uracilmethylphosphonate (5Umpa(2-) and 6Umpa(2-)) as acyclic nucleotide analogues are in the focus of anticancer and antiviral research. Connected metabolic reactions involve metal ions; therefore, we determined the stability constants of M(Umpa) complexes (M(2+)=Mg(2+), Ca(2+), Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). However, the coordination chemistry of these Umpa species is also of interest in its own right, for example, the phosphonate-coordinated M(2+) interacts with (C4)O to form seven-membered chelates with 5Umpa(2-), thus leading to intramolecular equilibria between open (op) and closed (cl) isomers. No such interaction occurs with 6Umpa(2-). In both M(Umpa) series deprotonation of the uracil residue leads to the formation of M(Umpa-H)(-) complexes at higher pH values. Their stability was evaluated by taking into account the fact that the uracilate residue can bind metal ions to give M(2)(Umpa-H)(+) species. This has led to two further important insights: 1) In M(6Umpa-H)-cl the H(+) is released from (N1)H, giving rise to six-membered chelates (degrees of formation of ca. 90 to 99.9 % with Mn(2+), Co(2+), Cu(2+), Zn(2+), or Cd(2+)). 2) In M(5Umpa-H)

METAL IONS AND HYDROGEN PEROXIDE XXIX. On the Kinetics and Mechanism of the Catalase-like Activity of Nickel(II) and Nickel(II)-Amine Complexes

-cl the (N3)H is deprotonated, leading to a higher stability of the seven-membered chelates involving (C4)O (even Mg(2+) and Ca(2+) chelates are formed up to approximately 50 %). In both instances the M(Umpa-H)-op species led to the formation of M(2)(Umpa-H)(+) complexes that have one M(2+) at the phosphonate and one at the (N3)(-) (plus carbonyl) site; this proves that nucleotides can bind metal ions independently at the phosphate and the nucleobase residues. X-ray structural analyses of 6Umpa derivatives show that in diesters the phosphonate group is turned away from the uracil residue, whereas in H(2)(6Umpa) the orientation is such that upon deprotonation in aqueous solution a strong hydrogen bond is formed between (N1)H and PO(3) (2-); replacement of the hydro gen with M(2+) gives the M(6Umpa-H)-cl chelates mentioned.

Connectivity patterns and rotamer states of nucleobases determine acid–base properties of metalated purine quartets

Abstract The disproportionation of H2O2, catalyzed by Ni2+ aq and several Ni2+−amine complexes, was investigated. (i) With Ni2+ aq in the pH range 6.6–8.2 and without buffer the following rate law holds: μ0 = d[O2/dt = k[Ni2+] [H2O2]2/[H+] (k = (1.77 ± 0.23) × 10−9 mol−1 1. sec−1). In the presence of phosphate buffer and in the pH range 6–7 the initial rate, μ0, is proportional to 1/[H+]. (ii) For the buffer-free Ni2+−2,2′-bipyridyl 1:1 system in the pH range 4.5–8 μ0 = ((k 1/[H+]) + k 2)[H2O2]([Ni2+]tot = [Bipy]tot)0.5 where k 1 = (1.35 ± 0.20) × 10−12 mol0.5 l.−0.5 sec−1 and k 2 = (2.5 ± 0.5) × 10−6 mol−0.5 l.0.5 sec−1. With borate buffer μ0 is increased, but in the pH-dependent part the given proportionalities between μ0 and [reactants] are valid. For these conditions the Ni2+−2,2′-bipyridyl 1:1 complex is the catalytically most active species. (iii) In the buffer-free system with Ni(ethylenediamine)2+ 2 as catalyst in the pH range 8.2–10 it appears that an analog rate law holds as given above for Ni2+...