Miloš I. Djuran

Intermolecular displacement of S-bound L-methionine on platinum(II) by guanosine 5′-monophosphate: implications for the mechanism of action of anticancer drugs

NMR investigations of the kinetics and thermodynamics of the competitive binding of L-methionine (Met), L-histidine (His), and 5′-monophosphates of guanosine (5′-GMP), adenosine (5′-AMP), thymidine (5′-TMP) and cytidine (5′-CMP) to [Pt(dien)Cl]+(dien = 1,5-diamino-3-azapentane) in aqueous solution show that 5′-GMP selectively displaces S-bound Met, a finding which has implications for DNA platination by anticancer drugs in vivo.

L-Methionine increases the rate of reaction of 5′-guanosine monophosphate with the anticancer drug cisplatin: mixed-ligand adducts and reversible methionine binding

L-Methionine (L-HMet) increased the rate of reaction of the anticancer drug cisplatin, cis-[PtCl2(NH3)2], with guanosine 5′-monophosphate (5′-GMP) at pH 7. The course of the reaction has been elucidated by 1H and [1H, 15N] NMR spectroscopy. Novel intermediates detected and characterized include cis-[Pt(5′-GMP-N7)(L-HMet-S)(NH3)2]2+ and [Pt(L-Met-S,N)(5′-GMP-N7)(NH3)]+(charges on 5′-GMP ignored), the formation of which involves ammine release. Monodentate S-bound L-HMet can co-ordinate reversibly, whereas S,N-chelated L-Met is much less reactive. Thus methionine residues in peptides and proteins could play a role in the transfer of Pt onto DNA. Comparative reactions of [Pt(en)Cl2](en = 1,2-diaminoethane) have also been investigated.

Crystal structures of Na[M(1,3-PDTA)]·3H2O(M = Cr, Rh; 1,3-PDTA = 1,3-propanediaminetetraacetate), and the absolute configuration of the (-)D-Isomer of the Rh complex

Abstract In order to clarify the relation between the absolute configuration and circular dichroism, and to investigate the influence of the size of metal ion on the strain in chelate rings of M(1,3-PDTA) complexes (M = Co, Cr, Rh; 1,3-DPTA = 1,3-propanediaminetetraacetate), X-ray crystal structure analysis of Na[Cr(1,3-PDTA)]·3H2O and (-)DNa[Rh(1,3-PDTA)]·3H2O were performed. The crystals of the two compounds are isomorphous and belong to the orthorhombic system, space group P212121, Z = 4, with cell dimensions a = 16.514(5), b = 8.809(2), c = 11,429(3) A and a = 16.511(13), b = 8.836(13), c = 11.431(7) A for chromium and rhodium complex, respectively. The structures were determined on the basis of 1699 and 2928 diffractometer data points, and were refined by least squares methods to R 0.053 and 0.025 for chromium and rhodium complexes respectively. Crystal structures consist of the complex and of the sodium ions and molecules of water. In the complex anion, the metal ion is coordinated octahedrally by a sexidentate 1,3-PDTA ligand. The six membered 1,3-propanediamine chelate T ring in both compounds takes a twist-boat δ conformation. Two equatorially-disposed glycinate G rings have an envelope λ conformation and two out-of-plane R rings are relatively flat. The absolute configuration of the Rh complex is Λ. The absolute configuration of the Cr complex, a crystal selected by chance from the optically-inactive complex, is also Λ. The ring strains were determined and compared with those in related Co(III) complexes.

Simple synthetic method and structural characteristics of (1,3-propanediaminetetraacetato)cobalt(II) complexes: uniform crystal packing in a series of metal(II) complexes with 1,3-propanediaminetetraacetate ligand

Abstract Starting from Ba[Ba(1,3-pdta)]·2H2O three new hexadentate cobalt(II) complexes [MII(H2O)6][CoII(1,3-pdta)]·2H2O (MII=Ba (1), Co (2) and Mg (3)) (where 1,3-pdta represents the 1,3-propanediaminetetraacetate ion) have been prepared and characterized. Presented in this paper, the crystal structures of the complexes containing CoII and MgII counter cations are isomorphic, as are the other crystal structures of metal(II) complexes with 1,3-pdta ligand, so far reported in the literature. The complexes crystallize in the space group Pnna of the orthorhombic crystal system. The structural unit consists of discrete [CoII(1,3-pdta)]2− and [MII(H2O)6]2+ octahedra, and two water solvent molecules all of which lie on a twofold axis of symmetry. The complex cations and anions alternate in the crystal lattice each being octahedrally surrounded by the counter ions. Electronic absorption spectra of [CoII(1,3-pdta)]2− complexes are presented and discussed in terms of octahedral distortion in edta-type CoII complexes.

Hydrolysis of amide bond in histidine-containing peptides promoted by chelated amino acid palladium(II) complexes: dependence of hydrolytic pathway on the coordination modes of the peptides

Abstract Hydrolytic reactions between cis-[Pd( l -Ala- N,O )Cl2]− and cis-[Pd( l -Ala- N,O )(H2O)2]+, in which l -Ala is alanine coordinated through N and O atoms, and N-acetylated peptides l -histidylglycine (MeCO-His-Gly), glycyl- l -histidine (MeCO-Gly-His), glycylglycyl- l -histidine (MeCO-Gly-Gly-His) and glycyl- l -histidylglycine (MeCO-Gly-His-Gly) were studied by 1H NMR spectroscopy. All reactions were carried out in the pH range 2.0–2.5 and two different temperatures, 22 and 60°C. In the reactions of these two palladium(II) complexes with MeCO-His-Gly, complete hydrolysis of the amide bond involving carboxylic group of histidine occurs in less than 24 h. The cleavage is regioselective. With peptides containing free a carboxylic group of histidine, MeCO-Gly-His and MeCO-Gly-Gly-His, palladium(II) complex promote the cleavage of the MeCO–Gly and Gly–Gly amide bonds. No cleavage of the Gly–His amide bond was observed. The mechanism of these hydrolytic reactions involves release of l -Ala ligand and aquation of the palladium(II) complex chelated to the substrate through the imidazole N-3 atom and deprotonated nitrogen atom of the amide bond involving amino group of histidine. This aqua complex represents a catalytically active form different from the initially added catalytically inactive complex. In the reactions of palladium(II) complexes with tripeptide MeCO-Gly-His-Gly, two amide bonds, MeCO–Gly and His–Gly, were cleaved. The mechanism of the cleavage of these amide bonds is correlated with two different palladium(II)–substrate catalytically active forms. These findings contribute to the better understanding of selective cleavage of peptides and proteins and must be taken into consideration in designing new reagents for this purpose.

Selective hydrolysis of the unactivated peptide bond in N-acetylated l-histidylglycine catalyzed by various palladium(II) complexes: dependence of the hydrolysis rate on the steric bulk of the catalyst

Abstract Hydrolytic reactions between various palladium(II) complexes of the type cis -[Pd(L)(H 2 O) 2 ] 2+ in which L is a chelating diamine (ethylenediamine, en; 1,2-propylenediamine, 1,2-pn; N -methylethylenediamine, Meen; isobutylenediamine, ibn and N,N,N′,N′ -tetramethylethylenediamine, Me 4 en) or S,N -coordinated amino acid ( S -methyl l -cysteine, MeS- l -HCys and l -methionine, l -HMet) and N -acetylated l -histidylglycine (MeCO-His-Gly), were studied by 1 H NMR spectroscopy. The reactions were carried out in the pH range 2.0–2.5 and at 60°C. In all these reactions, a palladium(II) complex bound to a histidine residue effects the regioselective cleavage of the amide bond involving the carboxylic group of histidine. We found that the rate of hydrolysis decreases as the steric bulk of the palladium(II) complex increases (en>1,2-pn>Meen>MeS- l -HCys>ibn>L-HMet>Me 4 en). The observed rates of hydrolytic reaction are discussed in terms of steric hindrance of the chelating diamine or sulfur-containing amino acid on the palladium(II) complexes. This study is an important step in the development of new palladium(II) complexes as artificial metallopeptidases.

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.

Binding of Platinum(II) to Some Biologicaly Important Thiols.

The reactions between [Pt(terpy)Cl+ and thiols, such as glutathione, L-cysteine, D-penicillamine and thioglycolic acid have been Studied by conventional UV-VIS spectrophotometry and H NMR spectroscopy. The second-ordero rate constants, K2, are similar for these four thiols, varying between 1.06 x 10-2 and 6.10 x 10+3 M-1 s-1 at 25°C. The activation entropies have large negative values between -100 and -200 J mol-1 which are compatible with an associative A mechanism. However, L-methionine, as thioether ligand, is unreactive under the same experimental conditions. The obtained results have been analyzed in relation to the antitumor activity and toxicity of platinum(II) complexes.

CIRCULAR DICHROISM AND ELECTRONIC ABSORPTION OF RHODIUM(III) EDTA-TYPE COMPLEXES: Ethylenediamine-N,N′-diacetato-N,N′-di-3-propionatorhodate(III) and (S,S)-Ethylenediamine-N,N′-disuccinatorhodate(III) Ions

Abstract Electronic absorption and CD spectra are reported for the sexidentate complexes, trans(O5)-Rh(EDDDA)−, trans(O5 O6)-Rh(EDDDA)−, and trans(O5)-Rh(S,S-EDDS)− (EDDDA)=ethylenediamine-N,N′-di-3-propionate; S,S-EDDS=(S,S)-ethylenediamine-N,N′-disuccinate). Because of the sterospecific coordination of the S,S-EDDS ligand the absolute configuration of (+)D-trans(O5)-Rh(S,S-EDDS)− is known to be Λ. By comparison of their CD spectra to that of the (+)D isomer of trans(O5)-Rh(S,S-EDDS)−, the absolute configurations of the (−)DEDDDA complexes are assigned tentatively.

Solid-state carbon-13 nuclear magnetic resonance investigations of bismuth citrate complexes and crystal structure of Na2[Bi2(cit)2]·7H2O

The complex Na2[Bi2(cit)2]·7H2O (H4cit = 3-carboxy-3-hydroxypentane-1,5-dioic acid) crystallized during reactions of the antiulcer drug ranitidine bismuth citrate with the tripeptide glutathione (γ-L-Glu-L-Cys-Gly) at low pH. X-Ray analysis showed one [Bi(cit)]– fragment per asymmetric unit with Bi3+ chelated to a terminal carboxylate group; citrate also binds, in tridentate mode, to the bismuth of an equivalent [Bi(cit)]– unit (related to the first by a C2 axis)via one oxygen donor from each of the remaining two carboxylate groups and the alkoxy group. Both ends of the resultant dimeric anion {Bi(µ-cit)2Bi}2– bind to adjacent dimers, related by n-glide plane symmetry, via double carboxylate bridges, to form a continuous polymeric anionic chain [{Bi(µ-cit)2Bi}n]2n– running throughout the crystal. In this way each bismuth atom achieves six-co-ordination [Bi–O 2.210(10)–2.505(10)A] with a nido-pentagonal-bipyramidal geometry, the vacant axial site providing evidence for a stereochemically active lone pair and the second axial site being occupied by the alkoxy donor. The parallel polyanionic chains are linked by anion–cation interactions [Na ⋯ O (cit) 2.37–2.50 A] and by bonds of largely ionic character (Bi ⋯ O 3.003–3.095 A) to give the overall three-dimensional solid-state structure which incorporates seven water molecules per dianionic subunit. The solid-state cross-polarization magic angle spinning 13C NMR spectrum of this complex is assigned with the aid of dipolar-dephasing and inversion-recovery cross-polarization experiments, and compared to those of ranitidine bismuth citrate and bismuth citrate Bi(Hcit). The IR and solid-state 13C NMR data suggested that the alkoxy group is protonated in Bi(Hcit) but deprotonated in ranitidine bismuth citrate, and that the latter contains similar dimeric units to Na2[Bi2(cit)2]·7H2O. The general modes of aggregration of dimeric [{Bi(µ-cit)2Bi}n]2n– units and the relevance to antiulcer activity are discussed.