New Tin (IV) and Organotin (IV) Complexes with a Hybrid Thiosemicarbazone/Hydrazone Ligand: Synthesis, Crystal Structure, and Antiproliferative Activity.

Nowadays, the search for new chemotherapeutic agents with low toxicity and high selectivity is a major concern. In this paper, we report the synthesis and characterization of a hybrid thiosemicarbazone/hydrazone ligand in its neutral form (L1H2) and as the chloride salt ([L1H3]Cl)-, three diorganotin (IV) complexes, and one complex with Sn (IV). The compounds have been fully characterized by IR, mass spectra, 1H, 13C, and 119Sn NMR, 119Sn CP/MAS NMR, and by single crystal X-ray diffraction. The organotin compounds have the empirical formula [SnR2L1] (R = Me, Bu, and Ph), but in the solid state, they are polymeric species with seven coordination number due to weak coordination of the pyridine nitrogen, whereas in solution, the polymeric structure is lost to afford hexacoordinate monomeric species. Reaction with SnI4 yields complex [Sn (L1)2]·EtOH, with the metal in a distorted dodecahedral arrangement. We have evaluated the antiproliferative activity of the two forms of the ligands and the four coordination compounds against MDA-MB-231, HeLa, PC3, and HepG2 cancer cell lines, and WI-38 normal cell line, and all the compounds present higher activity than cisplatin, used as the standard control. To investigate the mode of action, we have selected the most active complex, containing phenyl substituents, and used the triple negative breast cancer cell line MDA-MB-231. The results show that the complex induces apoptotic cell death promoted by generation of reactive oxygen species and by disruption of mitochondrial membrane potential.

Gold(III) bis(thiosemicarbazonate) compounds in breast cancer cells: Cytotoxicity and thioredoxin reductase targeting.

Gold(III) compounds have received increasing attention in cancer research. Three gold complexes of general formula [AuIIIL]Cl, where L is benzil bis(thiosemicarbazonate), compound 1, benzil bis(4-methyl-3-thiosemicarbazonate), compound 2, or benzil bis(4-cyclohexyl-3-thiosemicarbazonate), compound 3, have been synthesized and fully characterized, including the X-ray crystal structure of compound 3, confirming square-planar geometry around the gold(III) centre. Compound 1 showed moderate cytotoxicity and accumulation in MCF7 breast cancer cells but did not inhibit thioredoxin reductase (TrxR) activity and did not induce reactive oxygen species (ROS) production. Compound 2, the least cytotoxic, was found to be capable of modestly inhibiting TrxR activity and produced low levels of ROS in the MCF7 cell line. The most cytotoxic compound, 3, had the highest cellular accumulation and its distribution pattern showed a clear preference for the cytosol and mitochondria of MCF7 cells. It readily hampered intracellular TrxR activity leading to a dramatic alteration of the cellular redox state and to the induction of cell death.

Synthesis and antimicrobial activity of tetradentate ligands bearing hydrazone and/or thiosemicarbazone motifs and their diorganotin(IV) complexes.

Four novel ligands derived from 2,3-butanedione have been synthesized, two dissymmetric thiosemicarbazone/3-hydroxy-2-naphthohydrazone ligands, H2L1 (bearing 4-isopropyl-3-thiosemicarbazone) and H2L2 (containing 4-cyclohexyl-3-thiosemicarbazone) and the symmetric H2L3, diacetyl bis(3-hydroxy-2-naphthohydrazone), and H2L4, diacetyl bis(4-cyclohexyl-3-thiosemicarbazone). Their reactivity with SnR2Cl2 (R=methyl, n-butyl and phenyl) was explored and the resulting complexes were characterized by elemental analysis, molar conductivity, mass spectrometry, IR, 1H, 13C and 119Sn NMR and seven of them also by single crystal X-ray diffraction. The results showed that the reactivity of the dissymmetric ligands is strongly different and while the cyclohexyl derivative is very stable, with isopropyl easily undergoes a symmetrization reaction to yield the corresponding symmetric ligands. The antimicrobial activity of the ligands and the corresponding diorganotin(IV) complexes was investigated in vitro against seven species of microorganisms and minimum inhibitory concentrations (MICs) were determined. The results showed that the ligand H2L2 and several of its derivatives, together with methyl and phenyl complexes of H2L1, have the ability of inhibiting the growth of tested bacteria and fungi to different extents. Bacillus subtilis and Staphylococcus aureus Gram positive strains were the most sensitive microorganisms.

Antimicrobial activity of organotin(IV) complexes with the ligand benzil bis(benzoylhydrazone) and 4,4'-bipyridyl as coligand.

Several methyltin(IV) and butyltin(IV) complexes with the ligand benzil bis(benzoylhydrazone) and 4,4'-bipyridyl as coligand were synthesised and characterized by elemental analysis and by IR, (1)H, (13)C and (119)Sn NMR spectroscopies. Some of them were also analyzed using single crystal X-ray diffraction. The title compounds were evaluated for their in vitro antimicrobial properties. All buthyltin complexes showed significant inhibition of Gram positive bacteria, resulting Bacillus subtilis, Sarcina lutea and both methicillin-susceptible and methicillin-resistant Staphylococcus epidermidis the most sensitive strains. Furthermore, they were able to inhibit the growth of Gram negative bacteria, especially Proteus vulgaris, whereas no activity was exhibited against fungi. All methyltin complexes were devoid of antimicrobial properties.

Structural diversity of benzil bis(benzoylhydrazone): Mononuclear, binuclear and trinuclear complexes.

The coordination behaviour of the Schiff-base, benzil bis(benzoylhydrazone), LH(2) towards divalent nickel, lead, cadmium, zinc and copper ions has been investigated. The complexes have been fully characterized by techniques including (113)Cd and (207)Pb NMR, as well as (13)C and (113)Cd CP/MAS NMR and by single crystal X-ray diffraction. All the complexes have the general formula [ML](n) (n = 1-3 depending on the metal ion), with the ligand doubly deprotonated. The nickel complex [NiL] is a monomeric compound, the lead complex [PbL](2) shows a binuclear structure, whereas zinc [ZnL](3) and copper [CuL](3) complexes are trinuclear helicates. The cadmium complex seems to be a dimer with a structure similar to that of . In the nickel and lead derivatives, the ligand behaves as a tetradentate N(2)O(2) chelate and in complex also as a bridge through one of the O atoms. In the crystal structures of Zn and Cu complexes [ML](3) each metal is in a pentadentate N(3)O(2) environment formed by two different ligands, one tridentate chelate and the other bidentate chelate, giving rise to trinuclear helicates. These results point out the versatility of benzil bis(benzoylhydrazone) on its coordination.

Reactivity of thiosemicarbazides with redox active metal ions: controlled formation of coordination complexes versus heterocyclic compounds.

The reactions of 1,1-dimethyl-4-phenylthiosemicarbazide (LH) with Cu(II) and Sn(IV) have been investigated. If THF or methanol is used as solvent with Cu(II), oxidative cyclisation and coupling are observed, yielding a 1,2,4-thiadiazole or a 1,3,4-thiadiazolium salt. SnI(4) is also able to induce oxidative coupling of two thiosemicarbazide ligands, yielding 1,2,4-thiadiazolium or 1,2,4-triazolium salts, with I(3)(-) as the counterion, depending on the reaction conditions. By contrast, reaction of LH with SnI(4) in acetone yields a 1,3-thiazolium salt, with I(-) as counterion. Reaction with Cu(II) salts or SnI(4) in basic media leads to the formation of metal complexes containing two deprotonated thiosemicarbazide ligands. In the reaction of CuCl(2) in water in the presence of acid a complex containing two neutral ligands is obtained. Reactions with SnCl(4) are not able to induce ligand cyclisation, although a coordination compound with two neutral ligands was isolated from methanol.

Rhenium complexes with triazine derivatives formed from semicarbazones and thiosemicarbazones.

Benzil bis(semicarbazone), H2L(1), reacts with common rhenium(V) nitrido complexes such as [ReNCl2(PPh3)2] or [ReNCl2(PR2Ph)3] (R = Me, Et) under the release of one semicarbazone unit, cyclization, and formation of stable triazine-3-onato complexes of rhenium(V). The resulting 5,6-diphenyltriazine-3-one, HL (2), acts as monodentate or chelating, monoanionic ligand depending on the reaction conditions applied. Complexes of the compositions [ReNCl(L(2)-kappaN(2),kappaO)(PR2Ph)2] (R = Me, Et) or [ReN(L(2)-kappa N(2),O)(L(2)-kappaN(2))(PPh3)2] were isolated. The N(2) nitrogen atom is the preferred binding site of the monodentate form of the ligand. This contrasts the behavior of the analogous thione HL(3), which preferably coordinates to nitridorhenium(V) centers via the sulfur atom. HL(3) is readily formed by the abstraction of methanol from 5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione, H2L(3)OCH 3. In the presence of [ReNCl2(PPh3)2] or [ReNCl2(PR2Ph)3] complexes (R = Me, Et), this reaction yields stable complexes of the composition [ReN(L(3)-kappaN(2),kappaS)(L(3)-kappaS)(PR2Ph)2] (R = Me, Et, Ph) in good yields. Reduction of the metal atom and formation of the seven-coordinate [Re(PPh3)(L(3)-kappaN(2),kappaS)3] was observed during reactions of H2L(3)OCH3 with [ReOCl3(PPh3)2] or [ReO2I(PPh3)2], while no rhenium complexes could be isolated during similar reactions with H2L(1), although cyclization of the bis(semicarbazone) and the formation of H 2L(2)OEt were observed.

Diphenyllead(IV) chloride complexes with benzilthiosemicarbazones. The first bis(thiosemicarbazone) derivatives.

Reactions of diphenyllead(IV) chloride with benzil bis(thiosemicarbazone) (L1H6) and benzil bis(4-methyl-3-thiosemicarbazone) (L1Me2H4) afforded the first complexes containing the diphenyllead(IV) moiety with bis(thiosemicarbazone) ligands. The new complexes show diverse structural characteristics depending on the ligand and the working conditions. Complexes [PbPh2Cl(L1H5)].3H2O (1) and [PbPh2Cl(L1Me2H3)] (3) are mononuclear species in which the ligands are partially deprotonated and the lead atom has a C2N2S2Cl environment in a distorted pentagonal bipyramid coordination geometry. Complex [PbPh(L1Me2H2)](2).2H2O (4) was also obtained, which contains two lead atoms in a binuclear structure with a C2N2S3 coordination sphere for each lead atom, since both dideprotonated ligands act as N2S2 chelate and as sulfur bridge. Reaction from L1H6, in the same conditions in which complex 4 was prepared, gave a mixture of products: the lead (II) complex [Pb(L1H4)]2 (2) and [PbPh3Cl]n. Reactions with the cyclic molecules 5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]-triazine-3-thione (L2H2OCH3) and 5-methoxy-4-methyl-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]-triazine-3-thione (L2MeHOCH3) were also explored. In all the complexes, the ligands are deprotonated. The complexes [PbPh2(L2)2] (5) and [PbPh2(L2MeOCH3)2] (7) present the same characteristics. The X-ray structure of 5 shows a distorted octahedral geometry around the lead atom, with the ligand molecules acting as NS chelates, but the nitrogen bonded to the metal is different; one of the triazines shows a novel behavior, since the nitrogen atom of the new imine group formed is the one that is bonded to the lead center, being a good example of linkage isomerism. The complex [PbPh2Cl(L2)] (6), which was also isolated, could not be crystallized. All the complexes were characterized by elemental analysis, mass spectrometry, IR and 1H, 13C, and 207Pb NMR spectroscopy and some of them by X-ray diffraction studies.

Complexation versus thiadiazole formation for reactions of thiosemicarbazides with copper(II).

The reactions of N,N-substituted thiosemicarbazides with copper salts have been investigated and either copper(II) thiosemicarbazide complexes, 1,3,4-thiadiazolium salts or 1,3,5-thiadiazoles are obtained depending on the Cu(II) salt and solvent used.

Crystal structures of triazine-3-thione derivatives by reaction with copper and cobalt salts.

The reaction of 5-methoxy-5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione L1H2OCH3 with copper(II) chloride leads to the formation of an organic molecule L2 containing two triazine rings linked by a new S-S bond. A binuclear copper(II) complex, 1, containing L1 is also isolated. The reaction of L1H2OCH3 with copper(I) chloride yields a hexanuclear cluster of copper(I), 2, in which the copper atoms form a distorted octahedron with the ligand L1 acting as an NS chelate and sulfur bridge, giving to the copper ion a trigonal geometry by one N and two S atoms. In any reaction of the disulfide L2 with metal salts, complexes containing this molecule are isolated. Reactions with copper(I) and copper(II) chloride and nickel(II) and cadmium(II) nitrate produce the S-S bond cleavage, giving complexes containing the triazine L1 behaving as the NS anion, which show spectroscopic characteristics identical with those formed by reaction with L1H2OCH3. However, the reaction with cobalt(II) nitrate gives a low-spin octahedral cobalt(III) complex, in which an asymmetric rupture of the disulfide L2 has been produced, giving an unexpected complex with a new ligand and keeping the S-S bond.

Versatile chelating behavior of benzil bis(thiosemicarbazone) in zinc, cadmium, and nickel complexes.

Reactions of benzil bis(thiosemicarbazone), LH(6), with M(NO(3))(2).nH(2)O (M = Zn, Cd, and Ni), in the presence of LiOH.H(2)O, show the versatile behavior of this molecule. The structure of the ligand, with the thiosemicarbazone moieties on opposite sides of the carbon backbone, changes to form complexes by acting as a chelating molecule. Complexes of these metal ions with empirical formula [MLH(4)] were obtained, although they show different molecular structures depending on their coordinating preferences. The zinc complex is the first example of a crystalline coordination polymer in which a bis(thiosemicarbazone) acts as bridging ligand, through a nitrogen atom, giving a 1D polymeric structure. The coordination sphere is formed by the imine nitrogen and sulfur atoms, and the remaining position, in a square-based pyramid, is occupied by an amine group of another ligand. The cadmium derivative shows the same geometry around the metal ion but consists of a dinuclear structure with sulfur atoms acting as a bridge between the metal ions. However, in the nickel complex LH(6) acts as a N(2)S(2) ligand yielding a planar structure for the nickel atom. The ligand and its complexes have been characterized by X-ray crystallography, microanalysis, mass spectrometry, IR, (1)H, and (13)C NMR spectroscopies and for the cadmium complex by (113)Cd NMR in solution and in the solid state.