Bactericidal activity of different oxovanadium(IV) complexes with Schiff bases and application of chelation theory

Oxovanadium(IV) complexes have been synthesized and characterized the general composition [VOL(A)], where H₂L = salicylidene-o-aminothiophenol A¹ = bis(benzylidene)ethylenediamine, A² = bis(acetophenone)ethylenediamine, A³ = 2,2′-bipyridylamine, A⁴ = bis(benzylidene) ? 1,8-diaminonaphthalene, A⁵ = thiophene-o-carboxaldeneaniline and A⁶ = thiophene-o-carboxaldene-p-anisidine. Spectral studies indicate that the oxovanadium(IV) complexes assume a six-coordinate octahedral geometry. The antibacterial activities of the complexes against Salmonella typhi, Escherichia coli and Serratia mercescens are higher as compared to the free ligands, vanadyl sulphate, and the control (DMSO) but of moderate activity as compared to the standard drug (tetracycline).     

DFT analysis of the electronic structure of Fe(IV) species active in nitrene transfer catalysis: influence of the coordination sphere

Nitrene transfer reactions to various hydrocarbon molecules can be efficiently catalyzed by Fe complexes through a mechanism reminiscent of the oxygen transfer function of oxygenase enzymes. Such enzymes exhibit a high-valent iron oxo Fe(IV)?=?O as the active species, and it has also been proposed that an analogous species, i.e., Fe(IV)?=?NR (NR being the nitrene group) is responsible for the nitrene transfer activity. We describe here the influence of the Fe(IV) coordination sphere on some key parameters for nitrene transfer efficacy, such as the spin state of the Fe(IV) cation, the electronic affinity, and the bond dissociation energy of the NHR moiety. We explore here the electronic properties of Fe(IV)?=?NTs (NTs?=?tolylsulfonylimido group) mononuclear complexes with ligands involving phenolate and nitrogen donor groups, as catalytic properties with such ligands have been found to be quite promising. Six tetradentate ligands were studied, which derive from three different scaffolds: 2-methylenepyridine-N,N-bis(2-methylene-4,6-dichlorophenol) and 2-methylenepyridine-N,N-bis(2-methylene-4,6-dimethylphenol), N,N-dimethyl-N’,N’-bis(2-methylene-4,6-dichlorophenol) ethylenediamine, and N,N-dimethyl-N’,N’- bis(2-methylene-4,6-dimethylphenol) ethylenediamine, N,N’-bis(2-methylene-4,6-dichlorophenol)-N,N’-dimethyl-1,2-diaminoethane and N,N’-bis(2-methylene-4,6-dimethylphenol)-N,N’-dimethyl-1,2-diaminoethane. Thanks to thorough DFT computations, we present some rationalization of the electronic properties of the resulting Fe(IV)?=?NTs complexes in relation to their coordination sphere and compare them to other Fe(IV) nitrene active species. We show in particular the important role of the anionic character and strong π-donation of the phenolate groups.     

Synthesis, X-ray structure, and anti-leukemic activity of oxovanadium(IV) complexes

In a systematic effort to identify and develop effective anticancer agents, four oxovanadium(IV) complexes with 1,10-phenanthroline (Phen) or 4,7-dimethyl-1,10-phenanthroline (Me2-Phen) as ligand(s) were synthesized and characterized. Among the four oxovanadium(IV) complexes synthesized, the crystal structure of the bis(phenanthroline)oxovanadium(IV) complex bis(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Phen)2], compound 1) has been determined. Compound 1 crystallized in the space group P2(1)/n with unit cell parameters a = 14.2125(17) A, b = 10.8628(13) A, c = 20.143(2) A, alpha = 90 degrees, beta = 102.569(2) degrees, gamma = 90 degrees, V = 3035.3(6) A3, and Z = 4. The refinement of compound 1 by full-matrix least-squares techniques gave an R factor of 0.0785 for 4356 independent reflections. The structure contains two enantiomorphous molecules, lambda and delta, which are related by an inversion center. Compound 1 exhibited 3.5-fold more potent cytotoxic activity against NALM-6 human leukemia cells than the mono(phenanthroline)oxovanadium(IV) complex (diaqua)(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Phen)(H2O)2], compound 2) (IC50 values: 0.97+/-0.10 microM versus 3.40+/-0.20 microM: P=0.0004). Methyl substitution in the phenanthroline ligand enhanced the anti-leukemic activity of the mono(phenanthroline)oxovanadium(IV) complex 4.4-fold (IC50 values: 0.78+/-0.10 microM, compound 4, versus 3.40+/-0.20 microM, compound 2; P=0.0003) and the anti-leukemic activity of the bis(phenanthroline)oxovanadium(IV) complex 5.7-fold (IC50 values: 0.17+/-0.02 microM, compound 3, versus 0.97+/-0.10 microM, compound 1; P=0.001). The leading oxovanadium compound, bis(4,7-dimethyl-1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Me2-Phen)2], compound 3) triggered the production of reactive oxygen species (ROS) in human leukemia cells, caused G1-arrest and inhibited clonogenic growth at nanomolar concentrations.     

Chemical speciation of insulinomimetic VO(IV) complexes of pyridine-N-oxide derivatives: binary and ternary systems

In order to estimate the impact of the low-molecular-mass (l.m.m.) VO(IV) binders of blood serum on the potentially insulin-enhancing compound VO(HPO)(2) (HPO, 2-hydroxypyridine-N-oxide): and VO(MPO)(2) (MPO, 2-mercaptopyridine-N-oxide), the speciation in the binary system VO(IV)-HPO and VO(IV)-MPO and in the ternary systems VO(IV)-HPO(MPO)-ligand B (B=oxalate, lactate, citrate or phosphate) was studied by pH-potentiometry. The stability constants of the complexes formed were determined in aqueous solution at I=0.2 M (KCl) and T=25 degrees C. The most probable binding modes of the complexes were determined by EPR method. The pyridine-N-oxides were found to form very stable bis complexes, which are predominant in the pH range 2-7. The results in the ternary systems demonstrate that only the citrate is a strong enough VO(IV) binder to compete with the carrier ligands. The binding ability of the high-molecular-mass (h.m.m.) serum proteins albumin and transferrin were also assessed and transferrin was found to be an efficient binder molecule. The actual solution state of these compounds in blood serum is compared with that of other insulin-mimic VO(IV) complexes.     

Platinum(IV) chloride complexes with heterocyclic ligands

Platinum(IV) chloride complexes with heterocyclic ligands have been prepared and characterized by infrared and electronic spectra. The compounds are of general formula Pt(L)nCl4, where L = N-ethylimidazole, N-propylimidazole, isoxazole, 3,5-dimethylisoxazole, benzoxazole, 2-methylbenzoxazole, 2,5-dimethylbenzoxazole, ethylenediamine, n = 2, 4, and also Pt(enEt2)3Cl4 X 2H2O, where enEt2 = N,N-diethylethylenediamine. These complexes are hexacoordinate with cis or trans configuration. The antitumoral activity of some complexes in mice inoculated with leukemia L1210 is reported.     

Bis[platinum(II)] and bis[platinum(IV)] complexes with optically active bis(vicinal-1,2-diamines) and their interaction with DNA.

Bis[platinum(II)] [Cl2Pt(LL)PtCl2] complexes 2,5 and 8 with chiral non-racemic ligands: 1a-c (LL = (R,R), (S,S) and (R,S) N,N'-bis(3,4-diaminobutyl)hexanediamide); 4a,b (LL = (R,R) and (S,S) N,N'-bis[3,4-bis(diaminobutyl)] urea); 7a-d (LL' = (R,R), (S,S), (R,S) and (S,R) 4,5-diamino-N-(3,4-diaminobutyl) pentanamide) and bis[platinum(IV)] complex 10-13 with ligands 1a,b and 4a,b have been prepared and characterized by IR, 1H, 13C and 195Pt NMR spectra. The interactions of 2a-c, 5a, 5b, 8a-d and 10a with dsDNA were investigated with the goal of examining whether the chirality, the nature of the spacer and the oxidation state have an influence on platinum-DNA binding properties. All the bis[platinum(II)] complexes form with dsDNA intra- and interstrand crosslinks and crosslinks over sticky ends, whereas the bis[platinum(IV)] complex 10a only forms intra- and interstrand crosslinks. The platinum-DNA coordination sites were determined by the T4 DNA polymerase footprinting method. The results show that all investigated bis(platinum) complexes have high preference towards distinct purines. All isomeric bis(amide) 2a-c and mono(amide) 8a-d complexes exhibit nearly the same binding pattern, whereas the ureide complexes 5a and 5b have other coordination sites with higher sequence preference. Interestingly, the ureides 5a and 5b differ in their coordination sites not only in comparison to the bis(amides) 2a-c and mono(amides) 8a-d, but also between each other. The bis[platinum(IV)] complex 10a also differs in coordination sites in comparison to all the bis[platinum(II)] compounds.     

Model complexes for amavadine,a vanadium natural product

Amavadine is a vanadium natural product from the mushroom Amanita muscaria. Earlier reports have characterized the compound as a vanadyl (VO²⁺) complex with two N-hydroxy-αα-iminodipropionic acid ligands, but no hypothesis as to its function has yet been put forward. We report here the synthesis, isolation, and properties of bis(iminodiacetato)oxovanadium(IV) and bis(αα-iminodipropionato)oxovanadium(IV). The complex bis(ββ-iminodipropionato)oxovanadium(IV) has been prepared in solution. These complexes serve as models for Amavadine. The structures of the models are analogous to that of Amavadine, with two bidentate, singly charged ligands bonding through one oxygen and one nitrogen atom. The visible spectra suggest the possibility of 1:1 complexes in solution in addition to the 2:1 ligand to metal complexes. Preliminary electrochemical data suggest reversible V(IV) ? V(III) couples.     

Functional models for catechol dioxygenases: iron(III) complexes of cis-facially coordinating linear 3N ligands

A series of 1:1 iron(III) complexes of simple and sterically hindered tridentate 3N donor ligands have been synthesized and studied as functional models for catechol dioxygenases. All of them are of the type [FeLCl3], where L is bis(pyrid-2-yl-methyl)amine (L1), N,N-bis(benzimidazol-2-ylmethyl)amine (L2), N-methyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L3), N,N-dimethyl-N'-(pyrid-2-ylmethyl)-ethylenediamine (L4) and N-phenyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L5). They have been characterised by spectral and electrochemical methods. The X-ray crystal structure of the complex [Fe(L4)Cl3] has been successfully determined. The complex crystallizes in the triclinic space group P1 with a = 7.250(6), b = 8.284(3), c = 12.409(4) angstroms, alpha = 80.84(3) degrees, beta = 86.76(6) degrees, gamma = 72.09(7) degrees and Z = 2. It possesses a distorted octahedral geometry in which the L4 ligand is cis-facially coordinated to iron(III) and the chloride ions occupy the remaining coordination sites. The systematic variation in the ligand donor atom type significantly influences the Lewis acidity of the iron(III) center and hence the binding interaction of the complexes with simple and substituted catechols. The spectroscopic and electrochemical properties of the catecholate complexes generated in situ have been investigated. All the complexes catalyze mainly the oxidative intradiol cleavage of 3,5-di-tert-butylcatechol (H2DBC) in the presence of dioxygen, which is unexpected of the cis-facial coordination of the ligands. The rate of intradiol catechol cleavage reaction depends upon the Lewis acidity of iron(III) center and steric demand and hydrogen-bonding functionalities of the ligands. Interestingly, the electron-sink property of N-phenyl substituent in [Fe(L5)Cl3] complex leads to enhancement in rate of cleavage. All these observations provide support to the substrate activation mechanism proposed for intradiol-cleaving enzymes.     

Preparation and characterization of vanadyl complexes with bidentate maltol-type ligands; in vivo comparisons of anti-diabetic therapeutic potential

A series of 2-alkyl-3-hydroxy-4-pyrone oxovanadium(IV) compounds has been synthesized, characterized, and tested for bioactivity as potential insulin-enhancing agents. The vanadyl complexes, bis(maltolato)oxovanadium(IV), BMOV, bis(ethylmaltolato)oxovanadium(IV), BEOV, and bis(isopropylmaltolato)oxovanadium(IV), BIOV, were compared against vanadyl sulfate for glucose-lowering ability, when administered i.p. to STZ-diabetic rats, at a one-time dose of 0.1 mmol kg(-1)body weight. Blood levels of vanadium were determined at regular intervals, to 72 h, following i.p. injection. All complexes tested exceeded vanadyl sulfate in glucose-lowering ability; this effect was not correlated, however, with blood vanadium levels. Analysis of the pharmacokinetics of the disappearance of [ethyl-1-(14)C]BEOV after an oral gavage dose (50 mg kg(-1), 0.144 mmol kg(-1), in a 10 mL kg(-1) volume of 1% CMC solution) indicated clearly that metal ion-ligand dissociation took place relatively soon after oral ingestion of the complex. Half-lives of fast phase uptake and slow phase disappearance for (14)C and V were calculated from a two-compartment model for whole blood, plasma, liver, kidney, bone, small intestine, and lung, ranging from 17 min ( t(1/2)alpha for (14)C, liver) to 30 days ( t(1/2)beta for V, bone). Curves of disappearance of plasma and whole blood (14)C and V diverged dramatically within the first hour after administration of the vanadium complex.     

Solution equilibrium characterization of insulin-mimetic Zn(II) complexes

Solution speciation (stoichiometry and stability constants) of the insulin mimetic Zn(II) complexes of several bidentate ligands with (O,O), (N,O) or (S,O) coordination modes have been determined by pH-metry at 25 degrees Celsius and I=0.2M (KCl). All ligands were found to coordinate in a bidentate way forming mono, bis and tris complexes, besides a mixed hydroxo bis complex ZnL(2)(OH) detected in the slightly basic pH range together with the tris complex. Relationships between the stability data, lipophilicity of the complexes and earlier biological data are evaluated. The validity of the linear free energy relationships (LFER) between the proton and Zn(II) complexes and also between the VO(IV) and Zn(II) complexes is tested.     

Synthesis and cytotoxicity of new platinum(IV) complexes of mixed carboxylates

In order to develop new antitumor platinum(IV) complexes with highly tuned lipophilicity, a series of (diamine)Pt(IV) complexes of the formula [Pt(IV)(dach)L(3)L'] or [Pt(IV)(dach)L(2)L"(2)] (dach=trans-(+/-)-1,2-diaminocyclohexane; L=acetato, propionato; L'=acetato, propionato, valerato or pivalato; L"=trifluoroacetato) have been synthesized by electrophilic substitution of the tris(carboxylato)hydroxoplatinum(IV) complexes, [Pt(IV)(dach)L(3)OH] (L=acetato, propionato), with various carboxylic anhydrides such as acetic, trifluoroacetic, pivalic and valeric anhydrides. The present platinum(IV) complexes were fully characterized by means of elemental analyses, 1H NMR, mass and IR spectroscopies. The complexes 8 and 10, satisfying the appropriate range of lipophilicity (logP=0.18-1.54), exhibited high activity (ED(50), 5.1 and 1.3 microM, respectively) compared with other complexes, which implies that the lipophilicity is an important factor for the antitumor activity of this series of complexes.     

Comparison of anti-hyperglycemic effect amongst vanadium, molybdenum and other metal maltol complexes

A wide variety of vanadium-containing complexes have been tested, both in vivo and in vitro, as possible therapeutic agents for the oral treatment of type 2 diabetes mellitus. None so far has surpassed bis(maltolato)oxovanadium(IV) (BMOV) for glucose- and lipid-lowering in an orally available formulation. Ligand choice is clearly an important factor in pharmacological efficacy of vanadium compounds as insulin enhancing agents. In this study, we kept the ligand and dose the same, varying instead the metal ion bound to the maltolato ligand in a series of binary complexes of neutral charge. A requirement for vanadyl ion as the metal ion of choice was apparent; no other metal ion tested served as a suitable substitute. Amongst [MoO(2)](2+), Co(II), Cu(II), Cr(III), and Zn(II), only [MoO(2)](2+) and Co(II) showed any hypoglycemic activity at the ED(50) dose for bis(maltolato)oxovanadium(IV), 0.6 mmolkg(-1) by oral gavage in streptozotocin (STZ)-diabetic rats within 72 h of administration of compound.     

A new halogenated antidiabetic vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV): in vitro and in vivo insulinomimetic evaluations and metallokinetic analysis

A new vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV), VO(IPA)2, with a VO(N2O2) coordination mode, was prepared by mixing 5-iodopicolinic acid and VOSO4 at pH 5, with the structure characterized by electronic absorption, IR, and EPR spectra. Introduction of the halogen atom on to the ligand enhanced the in vitro insulinomimetic activity (IC50 = 0.45 mM) compared with that of bis(picolinato)oxovanadium(IV) (IC50 = 0.59 mM). The hyperglycemia of streptozotocin-induced insulin-dependent diabetic rats was normalized when VO(IPA)2 was given by daily intraperitoneal injection. The normoglycemic effect continued for more than 14 days after the end of treatment. To understand the insulinomimetic action of VO(IPA)2, the organ distribution of vanadium and the blood disposition of vanadyl species were investigated. In diabetic rats treated with VO(IPA)2, vanadium was distributed in almost all tissues examined, especially in bone, indicating that the action of vanadium is not peripheral. Vanadyl concentrations in the blood of normal rats given VO(IPA)2 remain significantly higher and longer than those given other complexes because of its slower clearance rate. VO(IPA)2 binds with the membrane of erythrocytes, probably owing to its high hydrophobicity in addition to its binding with serum albumin. The longer residence of vanadyl species shows the higher normoglyceric effects of VO(IPA)2 among three complexes with the VO(N2O2) coordination mode. On the basis of these results, VO(IPA)2 is indicated to be a preferred agent to treat insulin-dependent diabetes mellitus in experimental animals.     

Copper(II) complexes of tridentate pyridylmethylethylenediamines: role of ligand steric hindrance on DNA binding and cleavage

Copper(II) complexes of three linear unsymmetrical tridentate ligands viz. N-methyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L1), N,N-dimethyl-N'-(pyrid-2-ylmethyl)ethylenediamine (L2) and N,N-dimethyl-N'-((6-methyl)pyrid-2-ylmethyl)ethylenediamine (L3) have been isolated and characterized by elemental analysis, electronic absorption and EPR spectroscopy and cyclic and differential pulse voltammetry. Of these complexes [Cu(L2)Cl2] and [Cu(L3)Cl2] have been structurally characterized by X-ray crystallography. The [Cu(L2)Cl2] complex crystallizes in the monoclinic space group P2(1)/n with a=11.566(2) A, b=7.369(1) A, c=15.703(3) A, alpha=90 degrees , beta=109.68(8) degrees , gamma=90 degrees and Z=4 while [Cu(L3)Cl2] crystallizes in the triclinic space group P1 with a=9.191(2) A, b=12.359(3) A, c=14.880(3) A, alpha=79.61(13) degrees , beta=86.64(13) degrees , gamma=87.28(8) degrees and Z=2. The coordination geometries around copper (II) in these two complexes are best described as trigonal bipyramidal distorted square based pyramidal (TBDSBP). The distorted CuN3Cl basal plane in them is comprised of three nitrogen atoms of the meridionally coordinated ligand and a chloride ion and the axial position is occupied by the other chloride ion. The interaction of these complexes with Calf Thymus DNA (CT DNA) has been studied by using absorption, emission and circular dichroic spectral methods, thermal denaturation studies, viscometry and cyclic and differential pulse voltammetry. A strong blueshift in the ligand field band and a redshift in the ligand based bands of the copper(II) complexes on binding to DNA imply a covalent mode of DNA binding of the complexes, which involves coordination of most possibly guanine N7 nitrogen of DNA to form a CuN4 chromophore. This is supported by studying the interaction of the complexes with N-methylimidazole (N-meim), guanosine monophosphate (GMP), adenosine monophosphate (AMP) and cytidine (cytd) by ligand field and EPR spectral methods, which indicate the formation of a CuN4 chromophore only in the case of the more basic N-meim and GMP. The DNA melting curves obtained in the presence of copper(II) complexes reveal a monophasic and irreversible melting of the DNA strands and the high positive DeltaTm values (12-21 degrees C) also support the formation of strong Cu-N bonds by the complexes with DNA, leading to intra- and/or interstrand crosslinking of DNA. Competitive ethidium bromide (EthBr) binding studies show that the L2 and L3 complexes are less efficient than the L1 complex in quenching EthBr emission, which is consistent with their forming DNA crosslinking preventing the displacement of the DNA-bound EthBr. A very slight decrease in relative viscosity of DNA is observed on treating the L1 and L2 complexes with CT DNA; however, a relatively significant decrease is observed for the L3 complex suggesting that the length of the DNA fiber is shortened. DNA cleavage experiments show that all the complexes induce the cleavage of pBR322 plasmid DNA, the complex of L1 being more efficient than those of sterically hindered L2 and L3 ligands.     

Synthesis and biological activity of cis-dichloro mono- and bis(platinum) complexes with N-alkyl-ethylenediamine ligands

Mono- and bis(platinum) complexes containing N-alkyl-ethylenediamine units of the type {cis-PtCl₂[H₂NCH₂CH₂NH(CH₂)_nCH₃]} (n=8, 9, 11, 15) and [{cis-PtCl₂(H₂NCH₂CH₂NH)}₂(CH₂)_n] (n=6, 8, 10, 12) and their corresponding dihydroxo-platinum(IV) complexes were synthesized. The structures of the metal chelates were derived from elemental analyses and their ¹H, ¹³C, IR spectra. The length of the aliphatic chains has been varied systematically, in order to increase the lipophilicity. Enlargement of the linker could also lead to more flexibility of one platinum sphere in reference to the attached DNA species. Using in vitro cytotoxicity tests it is shown that the biological activity of the bis(platinum) complexes increased, up to n=12, with the length of the linker. The longest linker in the ligands resulted in the most effective bis(platinum) complexes against L1210 murine leukemia cells.     

The influence of a new vanadium compound, bis(2,2'-bipyridine)oxovanadium(IV) sulphate on liver golgi complexes from control and streptozotocin-diabetic rats.

Among the previously studied organic vanadium derivatives showing an anti-diabetic action, we investigated a new complex, bis(2,2'-bipyridine)oxovanadium(IV) sulphate. We tested its ability to normalise parameters previously described for streptozotocin (STZ)-diabetes, such as lower yields of Golgi-rich membrane fraction isolation, decreased activity of Golgi membrane marker enzyme - galactosyltransferase (GalT) - and altered morphology of rat liver Golgi complexes. Oral application as a drinking solution of 1.8 mmol bis(2,2'-bipyridine)oxovanadium(IV) (dissolved in 0.09 M NaCl) caused a similar dispersion of GalT activities in both vanadium treated groups, control and diabetic. Very low activities of the enzyme (characteristic for untreated diabetes) we found only in approximately 35 % of the STZ-diabetic rats treated with the new vanadium compound. The morphology of liver Golgi complexes in diabetic rats treated with bis(2,2'-bipyridine)oxovanadium(IV) sulphate was improved, which manifested itself in the reappearance of vacuoles with VLDL and coated and uncoated secretory vesicles. In view of biochemical and morphological parameters of normalised diabetic rat liver Golgi apparatus, the new vanadium complex was more effective than bis(oxalato)oxovanadium(IV) or bis(kojato)oxovanadium(IV), but in our experimental model, the best anti-diabetic, orally applied drug was the bis(maltolato)oxovanadium(IV) previously investigated.     

Structures of two N(1)-bound platinum(II)-6-oxopurine complexes. Comparisons with complexes derived from platinum (II) anti-tumor agents

The preparation and molecular structure of [(diethylenetriamine) (7,9-dimethylhypoxanthine) platinum(II)] (PF₆)₂·1.5H₂O and [(ethylenediamine) (7,9-dimethylhypoxanthine)₂platinum(II)] (PF₆)₂, are reported. These complexes represent the first structurally characterized N(1)-bound Pt(II) 6-oxopurine complexes. In each case, the Pt(II)N(1) bond length [2.051(6)A in the diethylenetriamine complex and 2.021(8)A in the ethylenediamine complex] indicates a strong metal-to-base binding. Both complexes contain interligand hydrogen bonds, with the ammine ligand acting as the donor and the O(6) atom of the base acting as the acceptor. These N(1)-bound complexes are compared with N(7)-bound 6-oxopurine and N(3)-bound cytosine complexes of Pt(II) anti-tumor agents.     

Iron and cobalt complexes with the ligand (2-aminoethyl)bis(2-pyridylmethyl)amine (uns-penp) and derivatives

A series of iron(II)/(III) and cobalt(II)/(III) complexes with the tetradendate tripodal ligands (2-aminoethyl)bis(2-pyridylmethyl)amine (uns-penp), its methylated derivatives Me₂-uns-penp and Me₄-uns-penp as well as the amide ligand N-acetyl-N,N-bis[(2-pyridyl)methyl]ethylenediamine (acetyl-uns-penp) were synthesized and structurally characterized. They have been investigated in regard to their reactivity towards dioxygen and/or hydrogen peroxide. Complexes of this type seem to have a high potential to be useful in the activation of dioxygen for selective oxidation reactions of organic substrates.     

Vanadyl-biguanide complexes as potential synergistic insulin mimics

Vanadium has well-documented blood-glucose-lowering properties both in vitro and in vivo. The design of new oxovanadium(IV) coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biguanides, most importantly metformin, are oral hypoglycemic agents used today to treat type 2 diabetes mellitus. In this study, biguanide, metformin, and phenformin, all biguanides, were coordinated to oxovanadium(IV) to form potential insulin-enhancing compounds. Highly colored, air-stable, bis(biguanidato)oxovanadium(IV), [VO(big)2], bis(N'N'-dimethylbiguanidato)oxovanadium(IV), [VO(metf)2], and bis(beta-phenethyl-biguanidato)oxovanadium(IV), [VO(phenf)2], were prepared. Solvation with dimethylsulfoxide occurred with VO(metf)2 to form a six-coordinate complex. Precursor ligands and oxovanadium(IV) coordination complexes were characterized by infrared spectroscopy, mass spectrometry, elemental analyses, magnetic susceptibility, and, where appropriate, 1H NMR spectroscopy. Biological testing with VO(metf)2, a representative compound, for insulin-enhancing potential included acute (72 h) administration, both by intraperitoneal (i.p.) injection and by oral gavage (p.o.) in streptozotocin (STZ)-diabetic rats. VO(metf)2 administration resulted in significant blood-glucose lowering at doses of 0.12 mmol kg-1 i.p. and 0.60 mmol kg-1 p.o. (previously established as ED50 doses for organically chelated oxovanadium(IV) complexes); however, no positive associative effects due to the presence of biguanide in the complex were apparent.     

Ethylenediamine-palladium(II) complexes with pyridine and its derivatives: synthesis, molecular structure and initial antitumor studies.

The synthesis of four mononuclear palladium complexes of general formula [Pd(en)Cl(L)]NO3 (en = ethylenediamine; L = pyridine (I), 4-methylpyridine (II), 4-hydroxypyridine (III) or 4-aminopyridine (IV) has been achieved. The structure of these compounds was studied by elemental analysis, IR, far-IR and 1H NMR; complex I was analyzed by X-ray diffraction. The crystal of [Pd(en)(pyridine)Cl]NO3 is monoclinic, space group P21/c (a = 7.990(2), b = 16.058(3), c = 9.846(2) A, beta = 103.81(3) degrees, Z = 4, R = 0.067, Rw = 0.066). The Pd(II) atom exhibits an approximately square planar coordination with bond lengths in the range 2.017-2.042 A for Pd-N and 2.320 A for Pd-Cl. In order to determine the donor strength of the aromatic pyridine ligands, the stability constants of binary complex ML2+ (M = [Pd(en) (H2O)2]2+; L = pyridine, 4-Me-pyridine, 4-OH-pyridine and 4-NH2-pyridine) were determined by potentiometric pH titration in aqueous solution (T = 25 degrees C, I = 0.1 mol l-1 NaNO3). The results show that the stability constants of the binary complexes systematically increase with increasing pKa of the pyridines. The above four palladium complexes, [Pt(en)(pyridine)Cl]NO3 and cis-diamminedichloroplatinum (II) (cis-DDP) were assayed for cytotoxicity in vitro against the human leukemia cell line HL-60, and compounds I, II, III and cis-DDP show significant cytotoxic activity against HL-60.