Snežana Rajković

Complex formation processes of terminally protected peptides containing two or three histidyl residues. Characterization of the mixed metal complexes of peptides

Copper(II), nickel(II) and zinc(II) complexes of the peptides Ac-HVVH-NH2 and Ac-HAAHVVH-NH2 have been studied by potentiometric, UV-vis, CD, EPR and NMR spectroscopic measurements. Both tetra and heptapeptides can form relatively stable macrochelates with copper(II), nickel(II) and zinc(II) ions, in which the ligands are coordinated via the side-chain imidazole functions. Formation of the macrochelates slightly suppresses, but cannot prevent the copper(II) and nickel(II) ion promoted deprotonation and coordination of the amide functionalities. The overall stoichiometry of the major species is [MH(-3)L]- with a 4N (=N-,N-,N-,Nim) coordination mode. In the case of Ac-HAAHVVH-NH2, coordination isomers of this species can exist with a preference for copper(II) or nickel(II) binding at the internal histidyl residue. In the copper(II)-Ac-HAAHVVH-NH2 system, the presence of the two anchoring sites results in the formation of dinuclear complexes. The existence of these species requires the involvement of amide functions in metal binding. Both equilibrium and spectroscopic data support the fact that the copper(II) ions of the dinuclear species are independent from each other providing a good chance for the formation of various mixed metal complexes. It was found that zinc(II) is not able to significantly alter the copper(II) binding of the heptapeptide, but it can occupy the uncoordinated histidyl sites. The formation of the copper(II)-nickel(II) mixed species was obtained in alkaline solutions and CD spectra suggest the statistical distribution of the two metal ions among the histidyl residues. The binding of HAAHVVH to palladium(II) is exclusive below pH 8 and the mixed metal species of palladium(II) and copper(II) ions are formed only in slightly basic solutions.

A study of the reactions of a methionine- and histidine-containing tetrapeptide with different Pd(II) and Pt(II) complexes: selective cleavage of the amide bond by platination of the peptide and steric modification of the catalyst

(1)H NMR spectroscopy was applied to the study of the reactions of [M(en)(H(2)O)(2)](2+) complexes (M = Pd(ii) and Pt(ii)) with the N-acetylated methionyl-glycyl-histidyl-glycineamide, MeCOMet-Gly-His-GlyNH(2). All reactions were performed in the pH range 1.5-2.0 with equimolar amounts of the [M(en)(H(2)O)(2)](2+) complex and the tetrapeptide at 60 degrees C. In all these reactions, a metal(ii) complex bound to a methionine residue affects the regioselective cleavage of the amide bond involving the carboxylic group of methionine. The priority in the cleavage of the Met-Gly amide bond in relation to the other amide bonds in this peptide is due to the high affinity of Pt(ii) and Pd(ii) ions for the sulfur donor atom. The mechanism of these hydrolytic reactions is discussed and, for its clarification, the reaction of the [Pd(en)(H(2)O)(2)](2+) complex with MeCOMet-Gly-His-GlyNH(2) was additionally investigated by potentiometric titration. The steric effects of the various palladium(ii) complexes of the type [Pd(L)(H(2)O)(2)](2+), in which L is a chelating diamine (ethylenediamine, en, 2-picolylamine, pic, or 2,2-dipyridylamine, dpa) on the hydrolytic cleavage of the amide bond involving the carboxylic group of histidine in the MeCOMet-Gly-His-GlyNH(2) tetrapeptide were also studied by (1)H NMR spectroscopy. All reactions were performed under the above-mentioned conditions and in the initial stage of these reactions, the MeCOMet-Gly-His-GlyNH(2) was reacted with an equimolar amount of the [Pt(dien)Cl](+) complex (dien is diethylenetriamine) and then the monoplatinated [Pt(dien)(MeCOMet-Gly-His-GlyNH(2)-S)](2+) complex was treated with an equimolar amount of [Pd(L)(H(2)O)(2)](2+). It was found that the rate of hydrolysis of the His-GlyNH(2) amide bond in [Pt(dien)(MeCOMet-Gly-His-GlyNH(2)-S)](2+) decreased from the en to the pic complex, with finally a total inhibition of this reaction with [Pd(dpa)(H(2)O)(2)](2+). These results are an important step in the study of the regioselective cleavage of peptides and proteins and in the development of new palladium(ii) complexes as artificial metallopeptidases.

Hydrolysis of the amide bond in methionine-containing peptides catalyzed by various palladium(II) complexes: Dependence of the hydrolysis rate on the steric bulk of the catalyst

(1)H NMR spectroscopy was applied to study the reactions of cis-[Pd(L)(H(2)O)(2)](2+) complexes (L is en, pic and dpa) with the N-acetylated tripeptides L-methionylglycylglycine, MeCOMet-Gly-Gly, and glycyl-L-methionyl-glycine, MeCOGly-Met-Gly. All reactions were performed in the pH range 2.0-2.5 with equimolar amounts of the cis-[Pd(L)(H(2)O)(2)](2+) complex and the tripeptide at 60 degrees C. The hydrolytic reactions of the cis-[Pd(en)(H(2)O)(2)](2+), cis-[Pd(pic)(H(2)O)(2)](2+) and cis-[Pd(dpa)(H(2)O)(2)](2+) complexes with MeCOMet-Gly-Gly were regioselective and only the amide bond involving the carboxylic group of methionine was cleaved. However, in the reactions of these three Pd(II) complexes with MeCOGly-Met-Gly, two amide bonds, Met-Gly and MeCO-Gly, were cleaved. From UV-Vis spectrophotometry studies, it was found that the rate-determining step of these hydrolytic reactions is the monodentate coordination of the corresponding Pd(II) complex to the sulfur atom of the methionine side chain. The rate of the cleavage of these amide bonds is dependent on the nature of the bidentate coordinated diamine ligand L (en>pic>dpa). The hydrolytic reaction of cis-[Pd(L)(H(2)O)(2)](2+)-type complexes with MeCOMet-Gly-Gly, containing the methionine side chain in the terminal position of the peptide, is regioselective while in the reaction of these Pd(II) complexes with MeCOGly-Met-Gly, none selective cleavage of the peptide occurs. This study contributes to a better understanding of the selective cleavage of methionine-containing peptides employing palladium(II) complexes as catalysts.

A comparative study of complex formation in the reactions of gold(III) with Gly-Gly, Gly-L-Ala and Gly-L-His dipeptides.

Proton NMR spectroscopy was applied to study the reactions of the dipeptides glycyl-glycine (Gly-Gly) and glycyl-L-alanine (Gly-L-Ala) with hydrogen tetrachloridoaurate(III) (H[AuCl(4)]). All reactions were performed at pH 2.0 and 3.0 and at 40 degrees C. The final products in these reactions were [Au(Gly-Gly-kappa(3)N(G1),N(G2),O(G2))Cl] and [Au(Gly-L-Ala-kappa(3)N(G),N(A),O(A))Cl] complexes. Tridentate coordination of the corresponding dipeptides and square-planar geometry of these Au(III) complexes was confirmed by NMR ((1)H and (13)C) spectroscopy. This study showed that at pH<3.0 the Au(III) ion was able to deprotonate the amide nitrogen atom. However this displacement reaction was very slow and the total concentration of the corresponding Au(III)-peptide complex formed after 5 days was less than 60% for the Gly-L-Ala or 70% for the Gly-Gly dipeptide. The kinetic data of the reactions between the Gly-Gly and Gly-L-Ala dipeptides and [AuCl(4)](-) were compared with those for the histidine-containing Gly-l-His dipeptide. The differences in the reactivity of these three dipeptides with the Au(III) ion are discussed.

Hydrolysis of the amide bond in histidine- and methionine-containing dipeptides promoted by pyrazine and pyridazine palladium(II)-aqua dimers: Comparative study with platinum(II) analogues

Two dinuclear palladium(II) complexes, [{Pd(en)Cl}2(μ-pz)](NO3)2 and [{Pd(en)Cl}2(μ-pydz)](NO3)2, have been synthesized and characterized by elemental microanalysis and spectroscopic (1H and 13C NMR, IR and UV-vis) techniques (en is ethylenediamine; pz is pyrazine and pydz is pyridazine). The square planar geometry of palladium(II) metal centers in these complexes has been predicted by DFT calculations. The chlorido complexes were converted into the corresponding aqua complexes, [{Pd(en)(H2O)}2(μ-pz)]4+ and [{Pd(en)(H2O)}2(μ-pydz)]4+, and their reactions with N-acetylated l-histidylglycine (Ac-l-His-Gly) and l-methionylglycine (Ac-l-Met-Gly) were studied by 1H NMR spectroscopy. The palladium(II)-aqua complexes and dipeptides were reacted in 1:1 M ratio, and all reactions performed in the pH range 2.0<pH<2.5 in D2O solvent and at 37°C. In the reactions of these complexes with Ac-l-His-Gly and Ac-l-Met-Gly dipeptides, the hydrolysis of the amide bonds involving the carboxylic group of both histidine and methionine amino acids occurs. The catalytic activities of the palladium(II)-aqua complexes were compared with those previously reported in the literature for the analogues platinum(II)-aqua complexes, [{Pt(en)(H2O)}2(μ-pz)]4+ and [{Pt(en)(H2O)}2(μ-pydz)]4+.

The reactions of [Au(dien)Cl]2+ with L-histidine-containing dipeptides. Dependence of complex formation on the dipeptide structure

Reactions between the monofunctional [Au(dien)Cl]2+ complex with L-histidine-containing dipeptides, L-histidyl-glycine (L-His-Gly), and glycyl-L-histidine (Gly-L-His) were studied by 1H NMR spectroscopy. All reactions were performed in aqueous solution at 3.50 pD 5.50 at ambient temperature. In reaction of [Au(dien)Cl]2+ with L-His-Gly, only 1 with N3-monodentate coordinated dipeptide was formed. The reaction was completed within 3 min and the complex was very stable during several days with no release of dien from Au(III). However, in the reaction of [Au(dien)Cl]2+ with Gly-L-His, depending on the pD, different Au(III)-dipeptide complexes were observed. When this reaction was carried out at 3.50 pD 4.50, only 4 with tridentate coordination of the dipeptide via the amino, deprotonated amide, and N3 imidazole nitrogen were observed after 4 days. However, during this time, at 4.50 < pD 5.50, two Au(III)-dipeptide products, 5 which represents an imidazole-bridged species along with the already described 4, were observed. The formation of these complexes proceeds through intermediates, 2 and 3 with N3-monodentate and NP,N3-bidentate coordinated dipeptide, respectively, and with complete loss of dien.

Coordination behaviour and two-dimensional-network formation in poly[[mu-aqua-diaqua(mu5-propane-1,3-diyldinitrilotetraacetato)dilithium(I)cobalt(II)] dihydrate]: the first example of an M(II)-1,3-pdta complex with a monovalent metal counter-ion.

The title compound, {[CoLi2(C11H14N2O8)(H2O)3].2H2O}n, constitutes the first example of a salt of the [M(II)(1,3-pdta)](2-) complex (1,3-pdta is propane-1,3-diyldinitrilotetraacetate) with a monopositive cation as counter-ion. Insertion of the Li+ cation could only be achieved through application of the ion-exchange column technique which, however, appeared unsuccessful with other alkali metals and the ammonium cation. The structure contains two tetrahedrally coordinated Li+ cations, an octahedral [Co(1,3-pdta)](2-) anion and five water molecules, two of which are uncoordinated, and is built of two-dimensional layers extending parallel to the (010) lattice plane, the constituents of which are connected by the coordinate bonds. O-H(water)...O hydrogen bonds operate both within and between these layers. The crystal investigated belongs to the enantiomeric space group P2(1) with only one (Lambda) of two possible optical isomers of the [Co(1,3-pdta)](2-) complex. A possible cause of enantiomer separation during crystallization might be the rigidification and polarization of the [M(1,3-pdta)](2-) core, resulting from direct coordination of Li+ cations to three out of four carboxylate groups constituting the 1,3-pdta ligand. The structure of (I) differs considerably from those of the other [M(II)(1,3-pdta)](2-) complexes, in which the charge compensation is realized by means of divalent hexaaqua complex cations. This finding demonstrates a significant structure-determining role of the counter-ions.

Hydrolysis of Methionine- and Histidine-Containing Peptides Promoted by Dinuclear Platinum(II) Complexes with Benzodiazines as Bridging Ligands: Influence of Ligand Structure on the Catalytic Ability of Platinum(II) Complexes

Dinuclear platinum(II) complexes, [{Pt(en)Cl}2(μ-qx)]Cl2·2H2O (1), [{Pt(en)Cl}2(μ-qz)](ClO4)2 (2), and [{Pt(en)Cl}2(μ-phtz)]Cl2·4H2O (3), were synthesized and characterized by different spectroscopic techniques. The crystal structure of 1 was determined by single-crystal X-ray diffraction analysis, while the DFT M06-2X method was applied in order to optimize the structures of 1–3. The chlorido Pt(II) complexes 1–3 were converted into the corresponding aqua species 1a–3a, and their reactions with an equimolar amount of Ac–L–Met–Gly and Ac–L–His–Gly dipeptides were studied by 1H NMR spectroscopy in the pH range 2.0 < pH < 2.5 at 37°C. It was found that, in all investigated reactions with the Ac–L–Met–Gly dipeptide, the cleavage of the Met–Gly amide bond had occurred, but complexes 2a and 3a showed lower catalytic activity than 1a. However, in the reactions with Ac–L–His–Gly dipeptide, the hydrolysis of the amide bond involving the carboxylic group of histidine was observed only with complex 1a. The observed disparity in the catalytic activity of these complexes is thought to be due to different relative positioning of nitrogen atoms in the bridging qx, qz, and phtz ligands and consequent variation in the intramolecular separation of the two platinum(II) metal centers.