Sotiris K. Hadjikakou

Palladium(II) and platinum(II) complexes of pyridine-2-carbaldehyde thiosemicarbazone with potential biological activity. Synthesis, structure and spectral properties. Extended network via hydrogen bond linkages of [Pd(PyTsc)Cl]

Abstract The reactions of Li2PdCl4 and Na2PtCl4 with pyridine-2-carbaldehyde thiosemicarbazone, HPyTsc, afforded the complexes [Pd(PyTsc)Cl], [Pd(PyTsc)2] and [Pt(PyTsc)Cl], [Pt(PyTsc)2]. The new complexes have been characterized by elemental analyses and spectroscopic studies. A crystal structure of [Pd(PyTsc)Cl] shows that the anion of PyTsc coordinates in a planar conformation to the central palladium(II) through the pyridyl N, azomethine N and thiolato S atoms. The planar molecules are linked into polymeric chains by N–H··N and N–H··S hydrogen bonding. The protonation constants of the ligand, Ka1 and Ka2, were determined by spectrophotometry and the logarithms of their values were found to be equal to 11.58±0.05 and 3.94±0.02 respectively. Correlation of the antitumor activity of these complexes to the structure and to reduction potential is reported. The compounds [Pt(PyTsc)2] and [Pd(PyTsc)2] were found to exhibit the higher in vivo antitumor activity and the lower cytotoxicity.

Synthesis, structural characterization and in vitro cytotoxicity of organotin(IV) derivatives of heterocyclic thioamides, 2-mercaptobenzothiazole, 5-chloro-2-mercaptobenzothiazole, 3-methyl-2-mercaptobenzothiazole and 2-mercaptonicotinic acid.

Five new organotin(IV) molecules with the heterocyclic thioamides; 2-mercaptobenzothiazole (Hmbzt), 5-chloro-2-mercaptobenzothiazole (Hcmbzt), 3-methyl-2-mercaptobenzothiazole (mmbzt) and 2-mercaptonicotinic acid (H(2)mna) of formulae [(n-C(4)H(9))(2)Sn(mbzt)(2)] (1), [(C(6)H(5))(2)Sn(mbzt)(2)] (2), [(CH(3))(2)Sn(cmbzt)(2)].1.7(H(2)O)] (3), [(n-C(4)H(9))(2)SnCl(2)(mmbzt)(2).(CH(2)Cl(2))] (4) and [[(C(6)H(5))(3)Sn](2)(mna).[(CH(3))(2)CO]] (5) have been synthesized and characterized by elemental analysis, 1H-, 13C-NMR, FT-IR and Mössbauer spectroscopic techniques. Crystal structures of molecules 1, 3 and 5 have been determined by X-ray diffraction at 173(1) K (1 and 5) and 293(2) K (3). Compound 1 C(22)H(26)N(2)S(4)Sn, is monoclinic, space group C2/c, a=44.018(2), b=8.8864(5), c=12.8633(7) A, beta=104.195(5) degrees, Z=8. Compound 3 is also monoclinic, space group P2(1)/c and a=17.128(2) A, b=17.919(2) A, c=7.3580(10) A, beta=98.290(10) degrees, Z=4. In both molecules 1 and 3, two carbon atoms from aryl groups, 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. Compound 5 C(45)H(39)NO(3)SSn(2) is monoclinic, space group P2(1)/n, a=9.1148(2) A, b=29.2819(6), c=15.5556(4) A, beta=106.2851(9) degrees, Z=4. Complex 5 contains two [(C(6)H(5))(3)Sn(IV)] moieties linked by a double deprotonated 2-mercaptonicotinic acid (H(2)mna). Both tin(IV) ions are five coordinated. This complex is the an example of a pentacoordinated Ph(3)SnXY system with an axial-equatorial arrangement of the phenyl groups at Sn(1) atom. Compounds 1, 3 and 5 were tested for in vitro cytotoxicity against the cancer cell line of sarcoma cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (benzo[a]pyrene) carcinogenesis. Compound 5 exhibits strong cytotoxic activity, while complexes 1 and 3 show less cytotoxic activity.

Synthesis and photochemical study of Cu(I) complexes with tri-p-tolylphosphine and heterocyclic thiones. The crystal structure of [CuCl(pymtH)(p-CH3C6H4)3P]2

Reactions of [Cu(tptp)X]4 (tptp=tri-p-tolyl-phosphine, XCl, Br or I) with heterocyclic thiones (L) [L=pyridine-2-thione (py2SH), pyrimidine-2-thione (pymtH), 1,3-thiazolidine-2-thione (tzdtH), 1-methyl- 1,3-imidazoline-2-thione (meimtH), benz-1,3-imidazoline-2-thione (bzimtH2) and quinoline-2-thione (qntH)] yield binuclear complexes of the general formula [Cu(tptp)(L)X]2. The complexes have been characterized by elemental analyses, IR, UV-Vis and 1H NMR spectroscopy. The photochemical behaviour of these complexes in chloroform solutions has been investigated. Irradiation causes the release of the phosphine and the formation of dinuclear compounds containing a Cu2S2 core. The crystal structure of [Cu(tptp)(pymtH)Cl]2 has been determined by single-crystal X-ray diffraction methods. The red crystals are triclinic, space group P with a=19.512(2), b=10.388(3), c=14.474(2) A, α=99.00(2), β=73.28(1), γ=116.22(2)°, Dcalc=1.394 M m−3, V=1228.2(4) A3 and Z=1. The molecule contains a planar Cu2S2 moiety with CuS bond lengths of 2.356(1) and 2.470(1) A. The CuP and CuCl distances are 2.227(1) and 2.300(1) A, respectively. The Cu···Cu separation is 3.316(0) A.

Synthesis, structural characterization and biological study of new organotin(IV), silver(I) and antimony(III) complexes with thioamides☆

An overview of our work on the synthesis and biological activity of a series of tin(IV), silver(I) and antimony(III) complexes with thioamides is reported. Organotin(IV) complexes of formulae (n-Bu)2Sn(MBZT)2 (1), Me2Sn(CMBZT)(2) (2), {(Ph3Sn)2(MNA) (Me2CO)} (3), Ph3Sn(MBZT) (4), Ph3Sn(MBZO) (5), Ph3Sn(CMBZT) (6), Ph2Sn(CMBZT)2 (7) and (n-Bu)2Sn(CMBZT)2 (8), Me2Sn(PMT)2 (9), (n-Bu)2Sn(PMT)2 (10), Ph2Sn(PMT)2 (11), Ph3Sn(PMT) (12) {where MBZT=2-mercapto-benzothiazole, CMBZT=5-chloro-2-mercapto-benzothiazole, H2MNA=2-mercapto-nicotinic acid, MBZO=2-mercapto-benzoxazole and PMTH=2-mercapto-pyrimidine} were characterized by spectroscopic (NMR, IR, Mossbauer, etc.) and X-ray diffraction techniques and their influence on the peroxidation of oleic acid was studied. They were found to inhibit strongly the peroxidation of linoleic acid by the enzyme lipoxygenase. In addition, organotin(IV) complexes were found to exhibit stronger cytotoxic activity in vitro, against leiomyosarcoma cells, than cisplatin. The antiproliferative activity of the organotin complexes studied, against leiomyosarcoma cells follow the same order of LOX activity inhibition. This is, 3>>12>7>6 approximately 8 approximately 10>5 approximately 4>>2>9. Thus, among organotin(IV)-CMBZT complexes, 7 exhibits higher activity than the others and this is explained by a free radical mechanism, as it is revealed by an EPR study. The results are compared with the corresponding ones found for the silver(I) complexes of formulae complexes {[Ag6(mu3-HMNA)4(mu3-MNA)2](2-).[(Et(3)NH)+]2.(DMSO)2.(H2O)} (13), {[Ag4Cl4(mu3-STHPMH2)4]n} (14), {[Ag6(mu2-Br)6(mu2-STHPMH2)4(mu3-STHPMH2)2]n} (15), {[Ag4(mu2STHPMH2)6](NO3)4}(n) (16), {[AgCl(TPTP)]4} (17), [AgX(TPTP)3] with X=Cl (18), Br (19), I (20) (where STHPMH2=2-mercapto-3,4,5,6-tetrahydro-pyrimidine, TPTP=tri(p-toly)phosphine) and those of antimony(III) complexes {[SbCl2(MBZIM)4](+).Cl(-).2H2O.(CH3OH)} (21), {[SbCl2(MBZIM)4]+.Cl(-).3H2O.(CH3CN)} (22), [SbCl3(MBZIM)2] (23), [SbCl3(EMBZIM)2] (24), [SbCl3(MTZD)2] (25), {[SbCl3(THPMT)2]} (26) and {[Sb(PMT)3].0.5(CH3OH)} (27) (where MBZIM is 2-mercapto-benzimidazole, EMBZIM=5-ethoxy-2-mercapto-benzimidazole and MTZD is 2-mercapto-thiazolidine), which they have characterized with similar techniques as in case of organotin(IV) complexes. Silver(I) and antimony(III) complexes were found to be cytotoxic against various cancer cell lines.

Synthesis, study and structural characterization of a new water soluble hexanuclear silver(I) cluster with the 2-mercapto-nicotinic acid with possible antiviral activity

Abstract Silver(I) chloride reacts with 2-mercapto-nicotinic acid (H2mna, C6H5NO2S) in the presence of an excess of triethylamine in DMSO to form a hexanuclear, water soluble, cluster of formula {[Ag6(μ3-Hmna)4(μ3-mna)2]2−·[(Et3NH)+]2·(DMSO)2·(H2O)} (1). The complex 1 was characterized by elemental analyses, and FT-IR, UV–Vis and 1H NMR spectroscopy. Crystal structures of complex 1 and the ligand, 2-mecapto-nicotinic acid (2), have been determined by X-ray diffraction. Compound 1, C52H68Ag6N8O15S8, is monoclinic with a space group P21/c (No. 14) and a=11.7080(10), b=16.2920(10), c=18.3010(10) A, β=91.350(10)°, Z=4. The entire molecule is ionic and consists of a double anionic hexa-nuclear cluster and two protonated triethylamine counter cations while it is solvated by two DMSO and one water molecule. The 2-mercapto-nicotinic acid (2), C6H5NO2S, is orthorhombic (space group Pna21 (No. 33), a=8.3910(10), b=13.2720(10), c=5.892 A, Z=4). An extended inter-molecular hydrogen bonding via O⋯HN contacts (O(1)⋯H(5)[N(5)]=1.8998, O(1)⋯N(5)=2.8049 A) links the molecules forming a supramolecular two-dimensional network. Complex 1, was evaluated for anti-HIV-RT activity. It was found to inhibit the human immunodeficiency viral replication reverse transcriptase (HIV-RT) with calculated inhibiting concentration (IC50) 0.01275±0.00115 mg ml−1.

Metal ion–drug interactions. Preparation and properties of manganese (II), cobalt (II) and nickel (II) complexes of diclofenac with potentially interesting anti-inflammatory activity: Behavior in the oxidation of 3,5-di-tert-butyl-o-catechol

Abstract Some new complexes of diclofenac with potentially interesting biological activity are described. The complexes of diclofenac [MnL 2 (H 2 O)], [CoL 2 (H 2 O) 2 ] · 0.5H 2 O, [CoL 2 (H 2 O)], [NiL 2 (H 2 O) 2 ] · 2H 2 O, and [NiL 2 ], were prepared by the reaction of the sodium salt, of a potent anti-inflammatory drug with MnCl 2 , CoCl 2 and NiCl 2 ·6H 2 O. Optical, EPR, infrared and electrochemical properties of these new complexes are reported. Both five and six-coordinated species were isolated in the solid state for Co(II). Both four and six-coordinated species were isolated in the solid state for Ni(II), while in DMF or MeOH solution predominant formation of six-coordinated species is observed for Co(II) and Ni(II) complexes. The ability of the complexes to catalyze the oxidation of 3,5-di- tert- butyl- o- catechol to 3,5-di- tert- butyl- o- quinone was studied by following the appearance of quinone spectrophotometrically. Correlation of the catalytic activity of these complexes to the reduction potential is reported.

Synthesis, structural characterization and biological studies of the triphenyltin(IV) complex with 2-thiobarbituric acid

The reaction between 2-thiobarbituric acid (H(2)TBA), which was treated with an equimolar amount of potassium hydroxide, in a water with triphenytin chloride in methanol, results in the formation of the {[Ph(3)Sn(O-HTBA)]}(n) (1) complex. Crystals of the hydrated 1 with formula {[Ph(3)Sn(O-HTBA)]·0.7(H(2)O)}(n) were growth from methanol/acetonitrile solution, of the white precipitation, filtered off, from the reaction. The crystal structure of complex 1 has been determined by X-ray diffraction at 120 K. Complex 1 is polymeric. The geometry around the tin(IV) ions is trigonal bi-pyramidal with coordination to three C atoms from phenyl groups and one O atom from a de-protonated HTBA ligand. Complex 1 and the already known [(n-Bu)(3)Sn(O-HTBA)·H(2)O] (2) were evaluated for their in vitro cytotoxic activity (cell viability) against human cancer cell lines: HeLa (cervical), OAW-42 (ovarian), MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), A549 (lung), Caki-1 (renal) and additionally, the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line MTSV17 with a Trypan Blue assay. Moreover complex 1 was evaluated for its in vitro cell growth proliferation activity against leiomyosarcoma cells (LMS), MCF-7 and MRC-5 cells with a Thiazolyl Blue Tetrazolium Bromide (MTT) assay. The type of cell death caused by complexes 1 and 2 was also evaluated by use of flow cytometry assay. The results showed that these compounds mediate a strong cytotoxic response to normal and cancer cell lines tested through apoptosis and induce cell cycle arrest in S phase of the cell cycle, suggesting DNA intercalation (direct or indirect) with the complexes. Finally, the influence of these complexes 1 and 2 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied.

Study of mixed ligand copper(I) complexes with tri-m-tolyl-phosphine (tmtp) and heterocyclic thiones. Crystal structures of bis[μ-S(benzimidazoline-2-thione)(tmtp) copper(I) chloride] and bis[μ-Br(thiazolidine-2-thione)(tmtp) copper(I)]

Reactions of [Cu(tmtp)X]n (tmtp=tri-m-tolyl-phosphine; X=Cl, Br) with heterocyclic thiones (L) (L=pyridine-2-thione (py2SH), pyrimidine-2-thione (pymtH), 1,3-thiazolidine-2-thione (tzdtH), 1-methyl-1,3-imidazoline-2-thione (meimtH), benz-1,3-imidazoline-2-thione (bzimtH2) and quinoline-2-thione (qntH)) yield binuclear complexes of the general formula [Cu(tmtp)(L)X]2. The complexes have been characterized by elemental analyses and their IR, UV-Vis and 1H NMR spectroscopic data. The photolysis of these complexes in dichloromethane solutions has been investigated. The crystal structures of [Cu(tmtp)(bzimtH2)Cl]2 (I) and [Cu(tmtp)(tzdtH)Br]2 (II) have been determined by single-crystal X-ray diffraction methods. The white crystals of the two compounds are both monoclinic, space group P21/a with a=12.636(8), b=15.325(6), c=13.696(8) A, β=102.76(3)°, Dcalc=1.421(1) Mg m−3, V=2586.5(3) A3 and Z=2 for [Cu(tmtp)(bzimtH2)Cl]2 and space group P21/n with a=15.085(1), b=9.820(3), c=17.263(1) A, β=99.77(3)°, Dcalc=1.494 Mg m−3, V=2520.2(4) A3 and Z=2 for [Cu(tmtp)- (thzdtH)Br]2. The chloro complex contains a planar Cu2S2 moiety with CuS bond lengths of 2.386(2) and 2.444(1) A and CuP and CuCl distances equal to 2.251(1) and 2.391(2) A, respectively. The Cu···Cu separation is 2.764(1) A. The bromo molecule forms a planar Cu2Br2 frame with CuBr bond lengths of 2.5182(2) and 2.5971(8) A and CuP and CuS distances equal to 2.240(1) and 2.307(1) A, respectively. The Cu···Cu separation is 3.3471(7) A. Rationalization of the above described properties in terms of stereoelectronic factors governing bond formation is attempted by means of EHT computations.

ANTI-INFLAMMATORY PROPERTIES OF DICLOFENAC TRANSITION METALLOELEMENT COMPLEXES

As part of our research into understanding drug-metalloelement interactions, we have prepared complexes of Cu(II), Co(II), Ni(II), Mn(II), Fe(II), Fe(III), and Pd(II) with Diclofenac, in order to investigate their anti-inflammatory activity. Their inhibitory effects on rat or mouse paw edema induced by Carrageenan, Con-A, Nystatin, and Bakers yeast were compared with those of Diclofenac. Furthermore, the action of Diclofenacs metalloelement complexes on phagocytosis of yeast by rat peritoneal cells, as well as the capacity of some of the metalloelement complexes to inhibit lipid peroxidation of liver microsomal membranes was also investigated. These complexes exhibited a strong inhibitory effect on Carrageenan-, ConA-, and Nystatin-induced edemas (35-80% inhibition) comparable to the inhibition caused by Diclofenac (61-76% inhibition). Furthermore, complexes with Co(II), Ni(II), Pd(II), and Mn(II) were found to have an anti-inflammatory profile (35-50% inhibition) superior to diclofenac (17% inhibition) when inhibiting inflammations due to Bakers yeast, the mechanism of which involves mainly the activation of lipoxygenase and/or complement system. Complexes of Ni(II) and Pd(II), which showed significant inhibition of induced-edemas in rats, were also tested in mice at lower and higher doses and showed a significant dose-dependent inhibition of edemas in mice. Some of these complexes also interfere with in vitro phagocytosis. The most active anti-inflammatory complexes Co(II), Pd(II), and Ni(II), also offered significant protection against lipid peroxidation in vitro, acting as antioxidant compounds, properties that are not demonstrated by Diclofenac. Finally, it is noted that almost all metalloelement complexes of Diclofenac showed high anti-inflammatory activity at molecular concentrations much lower than that of Diclofenac. From the present study it is suggested that the anti-inflammatory activity of Diclofenac is enhanced by the formation of coordination complexes with transition metalloelements.

Silver(I) complexes with heterocyclic thiones and tertiary phosphines as ligands. Part 4. Dinuclear complexes of silver(I) bromide: the crystal structure of bis[bromo-(pyrimidine-2-thione)(triphenylphosphine)silver(I)]

Abstract Mixed-ligand complexes of the formula [Ag(PPh 3 )(L)Br] 2 were obtained by treatment of various heterocyclic thiones L {L=pyridine-2-thione (py2SH), pyrimidine-2-thione (pymtH), benz-1,3-imidazoline-2-thione (bzimtH 2 ), benz-1,3-thiazoline-2-thione (bztztH), 1-methyl-1,3-imidazoline-2-thione (meimtH) and 5-methoxy-benz-1,3-imidazoline-2-thione (5MeObzimtH 2 )} with equivalent quantities of silver(I) bromide and triphenylphosphine in dry acetone. The compounds were characterized by their IR, far-IR, UV–Vis and 1 H NMR spectroscopic data. The crystal structure of [Ag(PPh 3 )(pymtH)Br] 2 was determined by single-crystal X-ray diffraction methods. The complex exhibits a planar Ag 2 Br 2 moiety in which each of the doubly bromine-bridged Ag(I) centres is further bonded to one phosphine P and one thione S atom.