Bert P. Operschall

Understanding the Acid-Base Properties of Adenosine : the Intrinsic Basicities of N1, N3 and N7

Adenosine (Ado) can accept three protons, at N1, N3, and N7, to give H(3) (Ado)(3+) , and thus has three macro acidity constants. Unfortunately, these constants do not reflect the real basicity of the N sites due to internal repulsions, for example, between (N1)H(+) and (N7)H(+). However, these macroconstants are still needed for the evaluations and the first two are taken from our own earlier work, that is, pK(H)(H(3))((Ado)) = -4.02 and pK(H)(H(2))((Ado)) = -1.53; the third one was re-measured as pK(H)(H)((Ado)) = 3.64 ± 0.02 (25 °C; I=0.5 M, NaNO(3)), because it is the main basis for evaluating the intrinsic basicities of N7 and N3. Previously, contradicting results had been published for the micro acidity constant of the (N7)H(+) site; this constant has now been determined in an unequivocal manner, and that of the (N3)H(+) site was obtained for the first time. The micro acidity constants, which describe the release of a proton from an (N)H(+) site under conditions for which the other nitrogen atoms are free and do not carry a proton, decrease in the order pk(N7-N1)(N7(Ado)N1·H)) = 3.63 ± 0.02 > pk(N7-N1)(H·N7(Ado)N1) = 2.15 ± 0.15 > pk(N3-N1,N7)(H·N3(Ado)N1,N7) =1.5 ± 0.3, reflecting the decreasing basicity of the various nitrogen atoms, that is, N1>N7>N3. Application of the above-mentioned microconstants allows one to calculate the percentages (formation degrees) of the tautomers formed for monoprotonated adenosine, H(Ado)(+) , in aqueous solution; the results are 96.1, 3.2, and 0.7% for N7(Ado)N1·H(+), (+)H·N7(Ado)N1, and (+)H·N3(Ado)N1,N7, respectively. These results are in excellent agreement with theoretical DFT calculations. Evidently, H(Ado)(+) exists to the largest part as N7(Ado)N1·H(+) having the proton located at N1; the two other tautomers are minority species, but they still form. These results are not only meaningful for adenosine itself, but are also of relevance for nucleic acids and adenine nucleotides, as they help to understand their metal ion-binding properties; these aspects are briefly discussed.

Probing the Metal-Ion-Binding Strength of the Hydroxyl Group

Introduction How Is the Extent of a Weak Interaction Best Quantified? Metal-Ion Complexes with Phosph(on)ate Groups as Primary Binding Sites Extent of the Hydroxyl−M2+ Interaction in Complexes of Hydroxymethylphosphonate Metal-Ion−Glycerol 1-Phosphate Systems: A Decreasing Solvent Polarity Favors Hydroxyl−M2+ Interactions Some Generalizations Regarding Phosph(on)ate Ligands with a Weakly Coordinating Second Site Metal-Ion Complexes with Carboxylate Groups as Primary Binding Sites Extent of Chelate Formation in Complexes of Hydroxyacetate and Related Ligands at I = 0.1 M Construction of the Reference Lines for Several M2+−Carboxylate Systems. Extent of Chelate Formation in Metal-Ion Complexes Formed with Hydroxy Carboxylates and Related Ligands Extent of Chelate Formation in Complexes of Hydroxyacetate-Type Ligands at I = 2 M Effect of Chelate-Ring Enlargement on the Hydroxyl−Metal-Ion Interaction Decreasing Solvent Polarity Favors the Hydroxyl−Metal-Ion Interaction in Complexes of Hydroxyacetate and Related O Ligands But Inhibits Thioether Interactions Metal-Ion Complexes with Amino Groups as Primary Binding Sites Estimation of Straight-Line Parameters for Complexes Formed with RCH2−NH2 Ligands Extent of Hydroxyl Group−Metal-Ion Binding in Complexes of 2-Aminoethanol and Related Ligands Comparison of the Metal-Ion-Binding Properties of 2-Aminoethanol and Triethanolamine Imidazole Residue as a Primary Binding Site in Ligands Containing also a Hydroxyl Group Pyridyl Nitrogen Is an Ideal Primary Metal-Ion-Binding Site for a Hydroxyl−Metal-Ion Interaction Isomeric Quantification of Metal-Ion Binding with Ligands Offering Two Hydroxyl Groups Effect of the Primary Binding Site on the Extent of the Hydroxyl−Metal-Ion Interaction Extent of Hydroxyl−Metal-Ion Interactions in Complexes Having a Bidentate Primary Binding Site Metal-Ion Complexes of Ligands with Two or More Hydroxyl Groups and at Least Four Binding Sites Complexes of the Alkaline EarthIons with Bistris and Some Related Buffers: Reduced Solvent Polarity Favors Metal-Ion−Hydroxyl Group Interactions Complexes of Several 3d and Related Metal Ions with Bistris and Derivatives Quest for Selectivity in Metal-Ion Coordination Involving Hydroxyl Groups General Conclusions

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.

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)

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)

-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

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 CH2OCH2P(O)

Metal ion complexes of nucleoside phosphorothioates reflecting the ambivalent properties of lead(II)

\rm{{_{2}^{-}}}

Intramolecular π-stacks in mixed-ligand copper(II) complexes formed by heteroaromatic amines and antivirally active acyclic nucleotide analogs carrying a hydroxy-2-(phosphonomethoxy)propyl residue‡

(OH) residue participates, next to the P(O)

Stability and Structure of Mixed-Ligand Metal Ion Complexes That Contain Ni2+, Cu2+, or Zn2+, and Histamine, as well as Adenosine 5′-Triphosphate (ATP4−) or Uridine 5′-Triphosphate (UTP4−): An Intricate Network of Equilibria

\rm{{_{2}^{-}}}

Extent of metal ion-sulfur binding in complexes of thiouracil nucleosides and nucleotides in aqueous solution

(OH) group, to some extent in Cu(Arm)2+ coordination, and that ππ 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)(RPO3) species, where RPO