E. R. Milaeva

Synthesis, structural characterization and in vitro cytotoxicity of new Au(III) and Au(I) complexes with thioamides

The reactions of tetrachloroauric(III) acid (HAuCl4) with the thioamides; 2-mercapto-benzothiazole (mbztH) and 5-ethoxy-2-mercapto-benzimidazole (EtmbzimH) lead to the desulfuration of the ligands and the formation of the ionic complexes {[AuCl4]- [bztH2]+} (1), and {[AuCl4]- [EtbzimH2]+ (H2O)} (2) (where bztH2+ and EtbzimH2+ are the desulfurated cations of the starting ligands). The reaction of HAuCl4 with 2-mercapto-nicotinic acid (mnaH2), however results in the formation of 2-sulfonate-nicotininc acid (C6H5NO5S) (3) with the simultaneous oxidation of the sulfur atom. On the other hand, the reactions of the gold(I) complex [Au(tpp)Cl] (4) (tpp = triphenylphosphine (Ph3P)) with the thioamides; 2-mercapto-thiazolidine (mtzdH), 2-mercapto-benzothiazole (mbztH) and 5-chloro-2-mercapto-benzothiazole (ClmbztH) in the presence of potassium hydroxide resulted in the formation of the gold(I) complexes of formulae [Au(tpp)(mtzd)] (5), [Au(tpp)(mbzt)] (6) and [Au(tpp)(Clmbzt)] (7) without ligand desulfuration. All complexes have been characterized by elemental analysis, FT-IR, far-FT-IR,1H-NMR, spectroscopic techniques and X-Ray crystallography. The electrochemical behavior of 1, 2 and 4-7 complexes and the ligands EtmbzimH, mbztH and mnaH2 was also studied in acetonitrile and DMF using cyclic voltammetry. The results are in support of a mechanism of desulfuration of the ligands by Au(III), involving a first oxidation of S to -SO3-, followed by a C-S bond cleavage. This is also supported by PM6 calculations of bond dissociation energies of the various compounds involved. Complexes 1, 2 and 4-7 were tested for in vitro cytotoxicity against leiomyosarcoma cells and the results are discussed in relation with the geometry of the complexes and compared with those of cisplatin and other metals. Complexes 1 and 5 showed higher activity than that of cisplatin, while HAuCl4 was inactive against sarcoma cells.

Structural Motifs and Biological Studies of New Antimony(III) Iodide Complexes with Thiones

Eight new antimony(III) iodide complexes of the heterocyclic thioamides, 2-mercapto-1-methylimidazole (MMI), 2-mercaptobenzimidazole (MBZIM), 5-ethoxy-2-mercaptobenzimidazole (EtMBZIM), 2-mercaptothiazolidine (MTZD), 3-methyl-2-mercaptobenzothiazole (NMeMBZT), 2-mercapto-3,4,5,6-tetrahydropyrimidine (tHPMT), 2-mercaptopyridine (PYT), and 2-mercaptopyrimidine (PMT) of formulas {[SbI(3)(MMI)(2)].MeOH} (1), [SbI(3)(MBZIM)(2)] (2), {[SbI(2)(mu(2)-I)(EtMBZIM)(2)](2).H(2)O} (3), [SbI(3)(MTZD)] (4), [(NMeMBZT)SbI(2)(mu(2)-I)(2)(mu(2)-S-NMeMBZT)SbI(2) (NMeMBZT)] (5), {[SbI(3)(tHPMT)(3)].MeOH} (6), [SbI(3)(PYT)] (7), and [SbI(3)(PMT)(2)] (8), have been synthesized and characterized by elemental analysis, FT-IR spectroscopy, FT-Raman spectroscopy, and TG-DTA analysis. The crystal structures of 3, 4, 5, 6, and 7 were also determined by X-ray diffraction. The complexes show interesting structural motifs. Complex 6 is a monomer, with octahedral (Oh) geometry around the metal ion formed by three sulfur and three iodide atoms. Complexes 3 and 5 are dimers, with a square pyramidal (SP) geometry in each monomeric unit, while complexes 4 and 7 are polymers with pseudotrigonal bipyramidal (psi-TBP). Two or three sulfur atoms from thioamide ligands and three iodide atoms are bound to Sb atoms forming building blocks for the dimers and polymers. Strong intramolecular interactions between mu(2)-I and/or mu(2)-S and Sb atoms stabilize both structures. In dimer complex 5, two terminal iodide and one terminal sulfur atom are bonded to the Sb ion, while two mu(2)-I and one mu(2)-S bridging atoms bridge the metal ions forming psi-Oh geometry. Computational studies using multivariant linear regression (MLR) and artificial neural networks (ANN) and considering biological results (50% inhibitory concentration, IC(50)) as dependent variables derived a theoretical equation for IC(50) values of the complexes studied. The calculated IC(50) values are compared satisfactorily with the experimental inhibitory activity of the complexes measured. Complexes 3-7 were used to study their influence upon the catalytic peroxidation of linoleic acid by the enzyme Lipoxygenase (LOX). Compounds 1-8 were also tested for in vitro cytotoxicity, and they showed mostly a moderate cytostatic activity against a variety of tumor cell lines but comparable with those found for the antimony(III) chloride and bromide complexes, reported earlier [Ozturk et al. Inorg. Chem. 2007, 46, 2861-2866; Ozturk et al. Inorg. Chem. 2009, 48, 2233-2245].

Synthesis, structural characterization and in vitro inhibitory studies against human breast cancer of the bis-(2,6-di-tert-butylphenol)tin(IV) dichloride and its complexes

Four new organotin(IV) complexes of bis-(2,6-di-tert-butylphenol)tin(IV) dichloride [(tert-Bu-)(2)(HO-Ph)](2)SnCl(2) (1) with the heterocyclic thioamides 2-mercapto-pyrimidine (PMTH), 2-mercapto-4-methyl-pyrimidine (MPMTH), 2-mercapto-pyridine (PYTH) and 2-mercapto-benzothiazole (MBZTH), of formulae {[(tert-Bu-)(2)(HO-Ph)](2)Sn(PMT)(2)} (2), {[(tert-Bu-)(2)(HO-Ph)](2)Sn(MPMT)(2)} (3), {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(PYT)} (4) and {[(tert-Bu-)(2)(HO-Ph)](2)SnCl(MBZT)} (5), have been synthesized and characterized by elemental analysis, (1)H-, (13)C-, (119)Sn-NMR, EPR, FT-IR, Raman and Mössbauer spectroscopic techniques. The crystal and molecular structures of compounds 1–5 have been determined by X-ray diffraction. The geometries around the metal center adopted in complexes 1–5 varied between tetrahedral in 1, trigonal bipyramidal in 3, 4, 5 and distorted octahedral in 2. Two carbon atoms from aryl groups and two chlorine atoms form a distorted tetrahedron in the case of 1. Two carbon, two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin(IV) with trans-C(2), cis-N(2), cis-S(2)-configurations in 2. However, in the case of 4 and 5 complexes two carbon, one sulfur, one nitrogen and one chloride atom form a distorted trigonal bipyramidal arrangement. Finally, in the case of 3 the trigonal bipyramidal geometry is achieved by two carbon, two sulfur and one nitrogen atom in a unique coordination mode of thioamides toward the tin(IV) cation. Compounds 1–5 were tested for their in vitro cytotoxicity against the human breast adenocarcinoma (MCF-7) cell line. Compound 3 exhibits strong cytotoxic activity against MCF-7 cells (IC(50) = 0.58 ± 0.1 μM).

Iron (III) porphyrin bearing 2,6-di-tert-butylphenol pendants deposited onto gold electrodes for amperometric determination of l-histidine

A sensitive amperometric sensor for determination of L-histidine was developed using gold electrode modified with Fe(III)-porphyrin bearing three 2,6-di-tert-butylphenol groups and one palmitoyl chain. Two methods of electrode modification were applied: direct chemisorption and embedment into dodecanethiol monolayer. Both types of electrodes were used for detection of L-histidine using Osteryoung square-wave voltammetry. The sensitivity of sensors presented towards L-histidine depends on the method of electrode modification. The detection limits observed for the electrodes incorporating with Fe(III)-porphyrin host by embedment and chemisorption were in 1 and 100 nM ranges, respectively. In addition, the determination of L-histidine with electrode modified by embedment technique was more precise, in comparison to that obtained by the direct chemisorption. Applicability of gold electrodes modified with Fe(III)-porphyrin for the direct electrochemical determination of L-histidine was demonstrated using the artificial matrix mimicking human serum.

Synthesis and antioxidative activity of metalloporphyrins bearing 2,6-di-tert-butylphenol pendants.

The novel metalloporphyrins (M=HH, Fe, Mn, Co, Cu, Zn) bearing 2,6-di-tert-butylphenol pendants as antioxidant substituents, and a long chain hydrocarbon palmitoyl group have been synthesized. The oxidation of compounds by PbO2 leads to the formation of the corresponding 2,6-di-tert-butylphenoxyl radicals studied by EPR. The activity of porphyrins in lipid peroxidation has been examined using (1) in vitro lipid peroxidation induced by tert-butylhydroperoxide in respiring rat liver mitochondria, (2) in vitro lipid peroxidation in liver homogenates of Wistar strain rats, and (3) a model process of peroxidation of (Z)-octadec-9-enic (oleic) acid as a structural fragment of lipids. The activity of these compounds depends dramatically on the nature of metal and might be changed from antioxidative (M=HH, Mn, Cu, Zn) to indifferent (M=Co), and to pro-oxidative one (M=Fe). The anti- or pro-oxidative action of these compounds may be derived from the concurrence between the involvement of 2,6-di-tert-butylphenol pendants acting as radical scavengers and redox active metal center promoting oxidation processes. The results of this study suggest that the polytopic compounds combining in one molecule 2,6-di-tert-butylphenol pendants, metalloporphyrin moiety, and a palmitoyl group, are membrane active compounds and might be studied in an effort to find novel pharmaceutical agents.

Organic Derivatives of Mercury and Tin as Promoters of Membrane Lipid Peroxidation

The toxicity mechanisms of mercury and tin organic derivatives are still under debate. Generally the presence of organic moieties in their molecules makes these compounds lipophilic and membrane active species. The recent results suggest that Hg and Sn compounds deplete HS-groups in proteins, glutathione and glutathione-dependent enzymatic systems; this process also results in the production of reactive oxygen species (ROS), the enhancement of membrane lipids peroxidation and damage of the antioxidative defence system. The goal of this review is to present recent results in the studies oriented towards the role of organomercury and organotin compounds in the xenobiotic-mediated enhancement of radical production and hence in the promotion of cell damage as a result of enhanced lipids peroxidation. Moreover the conception of the carbon to metal bond cleavage that leads to the generation of reactive organic radicals is discussed as one of the mechanisms of mercury and tin organic derivatives toxicity. The possible use of natural and synthetic antioxidants as detoxification agents is described. The data collected recently and presented here are fundamentally important to recognizing the difference between the role of metal center and of organic fragments in the biochemical behavior of organomercury and organotin compounds in their interaction with primary biological targets when entering a living organism.

Antioxidative Activity of Ferrocenes Bearing 2,6-Di-Tert-Butylphenol Moieties

The antioxidative activity of ferrocenes bearing either 2,6-di-tert-butylphenol or phenyl groups has been compared using DPPH (1,1-diphenyl-2-picrylhydrazyl) test and in the study of the in vitro impact on lipid peroxidation in rat brain homogenate and on some characteristics of rat liver mitochondria. The results of DPPH test at 20°C show that the activity depends strongly upon the presence of phenolic group but is improved by the influence of ferrocenyl fragment. The activity of N-(3,5-di-tert-butyl-4-hydroxyphenyl)iminomethylferrocene (1), for instance, was 88.4%, which was higher than the activity of a known antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT) (48.5%), whereas the activity of N-phenyl-iminomethylferrocene 2 was almost negligible −2.9%. The data obtained demonstrate that the compounds with 2,6-di-tert-butylphenol moiety are significantly more active than the corresponding phenyl analogues in the in vitro study of lipid peroxidation in rat brain homogenate. Ferrocene 1 performs a promising behavior as an antioxidant and inhibits the calcium-dependent swelling of mitochondria. These results allow us to propose the potential cytoprotective (neuroprotective) effect of ditopic compounds containing antioxidant 2,6-di-tert-butylphenol group and redox active ferrocene fragment.

Cryoprotective effect of phosphorous-containing phenolic anti-oxidant for the cryopreservation of beluga sperm

A cryoprotective effect of an addition of a new synthetic antioxidant - a representative of phosphorus-containing sterically hindered phenols is presented. The efficiency of the compound was shown to exceed the effect of lipid-soluble antioxidants butylated hydroxytoluene (BHT) and trolox in the conditions of cryopreservation of beluga sperm in the presence of the modified Steins medium. It was shown that the level of carbonyl oxidation by-products, which can react with thiobarbituric acid (TBARS), in beluga sperm was inversely proportional to the motility time of sperm cells. The fertility of beluga sperm increased 2 times upon the addition of phosphorus-containing phenol to a modified Steins medium. The prospects of the new antioxidant application to improve cryoresistance of beluga sperm in the conditions of cryopreservation for its efficient protection from the peroxidation processes are discussed.

Comparative study of redox characteristics and antioxidant activity of porphyrins with 2,6-dialkylphenol groups

152 The oxidative stress of an organism is a result of the acceleration of lipid peroxidation (LPO) in cells and the formation of reactive oxygen species and free rad icals. This process leads to destruction of membranes, the emergence of numerous pathologies, and prema ture aging of the organism. The search for new antiox idants, as well as for methods to assess the antioxidant activity, is an important and interesting task [1]. Of particular interest are synthesis and study of properties of polyfunctional compounds with several pharma cophoric centers in the molecule, because such a com bination is able not only to enhance the known physi ological activity but also to cause the appearance of new types of physiological activity [2–4]. Ionol I (2,6 di tert butyl 4 methylphenol) is a known anti oxidant used in the manufacture of foodstuffs (food additive E321). 2,6 Diisobornyl 4 methylphenol (dibornol) IV is currently undergoing preclinical tri als as a promising drug [5]. CHEMISTRY

Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents

A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16μM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4μM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3μM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons.