C.N. Banti

Synthesis, characterization and biological studies of new antimony(III) halide complexes with ω-thiocaprolactam.

Three new antimony(III) halide complexes (SbX(3), X=Cl, Br and I) with the heterocyclic thione ω-thiocaprolactam (1-azacycloheptane-2-thione, (Hthcl)) of formulae {[SbCl(2)(μ(2)-Cl)(Hthcl)(2)](n)} (1), {[(SbBr(2)(μ(2)-Br)(Hthcl)(2))(2)]} (2) and {[(SbI(2)(μ(2)-I)(Hthcl)(2))(2)]} (3) were synthesized from the reaction of antimony(III) halides with ω-thiocaprolactam in 1:2 stoichiometry. The complexes were characterized by elemental analysis, FT-IR spectroscopy, (1)H, (13)C NMR spectroscopy and Thermal Gravimetry-Differential Thermal Analysis (TG-DTA). Crystal structures of the ligand ω-thiocaprolactam and its complexes 1-3 were determined with single crystal X-ray diffraction analysis. Complexes 1-3 and ω-thiocaprolactam were evaluated for their in vitro cytotoxic activity against leiomyosarcoma (LMS) and human breast adenocarcinoma (MCF-7) tumor cell lines. Antimony complexes 1-3 exhibit strong antiproliferative activity against both cell lines tested. The higher such activity was found for 3 with IC(50) values of 0.12±0.04 μM (LMS) and 0.76±0.16 μM (MCF-7) which are 60 and 10 times respectively, stronger than that of cisplatin. The influence of these complexes 1-3 and ω-thiocaprolactam upon the catalytic peroxidation of linoleic acid to hyperoxolinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. The results were shown negligible inhibitory activity of 1-3 against LOX.

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).

New antimony(III) halide complexes with dithiocarbamate ligands derived from thiuram degradation: The effect of the molecule's close contacts on in vitro cytotoxic activity

Antimony(III) halide complexes of the formulae {[SbBr(Me2DTC)2]n} (1), {[SbI(Me2DTC)2]n} (2) and {[(Me2DTC)2Sb(μ2-I)Sb(Me2DTC)2](+).I3(-)} (3) (Me2DTC = dimethyldithiocarbomate) were synthesized from SbX3, (X = Br or I) and tetramethylthiuram monosulfide (Me4tms) or tetramethylthiuram disulfide (Me4tds). The complexes were characterized by melting point (m.p.), elemental analysis (e.a.), Fourier-transform Infra-Red (FT-IR), Fourier-transform Raman (FT-Raman), Nuclear Magnetic Resonance ((1)H,(13)C-NMR) spectroscopy and Thermogravimetric-Differential Thermal Analysis (TG-DTA). Crystal structures of complexes 1-3 were determined with single crystal X-ray diffraction analysis. Complexes 1 and 2 are polymers with distorted square pyramidal (SP) geometry in each monomeric unit, whereas complex 3 is ionic, containing an iodonium linkage Sb-I(+)-Sb and an I3(-) counter anion; to the best of our knowledge, this is the first ionic antimony(III) iodide complex. The in vitro cytotoxic activity of 1-3 against human adenocarcinoma cells: breast (MCF-7) and cervix (HeLa) cells and non-cancerous cells: MRC-5 (normal human fetal lung fibroblast cells) was evaluated with trypan blue (TB) and sulforhodamine B (SRB) assays. Among antimony(III) compounds with sulfur containing ligand, those of dithiocarbamates exhibit significant cytotoxic activity. Hirshfeld surface volumes were analyzed to clarify the nature of the intermolecular interactions by the 2D fingerprint plot. Molecules with lower H-all atoms inter-molecular interactions exhibit the higher activity against MCF-7 cells. The in vivo genotoxicity of 1-3 was evaluated by the mean of Allium cepa test. Alterations in the mitotic index values due to the chromosomal aberrations were observed in the case of complexes 2 and 3. Since, no such alteration is caused by 1, it makes this compound candidate for further study as potential drug.

Structural and In Vitro Biological Studies of Organotin(IV) Precursors; Selective Inhibitory Activity Against Human Breast Cancer Cells, Positive to Estrogen Receptors

Crystals of Ph3SnCl (1) were grown from a methanol/acetonitrile solution. Compounds [Ph3SnOH]n (2) and [(Ph2Sn)4Cl2O2(OH)2] (3) were crystallized from diethyl ether/methanol/acetonitrile and hot acetone/water solutions respectively, of the white precipitation, formed by adding KOH to solutions of 1 and [Ph2SnCl2] in 1 : 1 and 1 : 2 molar ratios respectively. Complex 1 was characterized by X-ray crystallography. X-ray structure determination of compounds 2 and 3 confirmed the previously reported identities. The molecular structure of 1, reported here, is a new polymorphic form of the known one for Ph3SnCl. Four independent [Ph3SnCl] molecules constitute the crystal structure of 1. The moieties are packed in two pairs in a tail-to-tail arrangement. Complexes 1–3 were evaluated for their in vitro cytotoxic activity (cell viability) against human cancer cell lines: HeLa (human cervical), MCF-7 (breast, estrogen receptor (ER) positive), MDA-MB-231 (breast, ER negative), A549 (lung), Caki-1 (kidney carcinoma), 786-O (renal adenocarcinoma), K1 (thyroid carcinoma), and the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) versus, the normal immortalized human mammary gland epithelial cell line MTSV17 with a sulforhodamine B (SRB) assay. The results show potent cytotoxic activity of the complexes against all cell lines used, which was superior to that of cisplatin (CDDP). Compounds 1–3 showed higher activity against breast cancer cells MCF-7 (ER positive) than against of MDA-MB-231 (ER negative). These findings prompted us to search for possible interaction of these complexes with other cellular elements of fundamental importance in cell proliferation. The influence of these complexes 1–3 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX), as well as their binding affinity towards calf thymus-DNA, were kinetically and theoretically studied.

Silver(I) compounds of the anti-inflammatory agents salicylic acid and p-hydroxyl-benzoic acid which modulate cell function

Silver nitrate reacts with salicylic acid (salH2) or p-hydroxy-benzoic acid (p-HbzaH2) and equimolar amount of NaOH to yield a white precipitations which are then treated with tri(p-tolyl)phosphine (tptp) or tri(m-tolyl)phosphine (tmtp) to yield the complexes [Ag(tptp)2(salH)] (1), [Ag(tptp)2(p-Hbza)] (2) and [Ag(tmtp)2(salH)] (3). Complexes 1 and 3 are also obtained when aspirin (aspH) is used. The acetic ester of salicylic acid is hydrolyzed to form the complexes 1 and 3. However, when aspirin and tptp are used, a mixture of products was obtained which contains both 1 and an ionic complex of formula {[Ag(tptp)4](+)[(salH)(-)]∙[(CH3)2NCHO)]∙(H2O)} (1a). The complexes were characterized by m.p., e.a., mid-FT-IR, (1)H-,(31)P-NMR, HRMS, UV-vis spectroscopic techniques and X-ray crystallography. Two phosphorus and one carboxylic oxygen atoms form a trigonal planar geometry around Ag(I) ions in complexes 1-3. Complex 1a consists of a [Ag(tptp)4](+) cation and a deprotonated salH(-) counter anion. The influence of 1-3 on the viability of MCF-7 (breast) and HeLa (cervix) adenocarcinoma cells, is evaluated. DNA binding tests indicate the ability of 1-3 to modify the activity of cells. The binding constants of 1-3 towards calf-thymus DNA, reveal stronger interaction of 2. Changes in fluorescent emission light of ethidium bromide (EB) in the presence of DNA suggest intercalation or electrostatic interactions into DNA for 1 and 3. Docking studies on DNA-complex interactions confirm the binding of 1-3 in the minor groove of B-DNA. Moreover, the influence of 1-3 on the peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied.

Nimesulide Silver Metallodrugs, Containing the Mitochondriotropic, Triaryl Derivatives of Pnictogen; Anticancer Activity against Human Breast Cancer Cells

Novel silver(I) metallo-drugs of the nonsteroidal anti-inflammatory drug nimesulide (nim) and the mitochondriotropic triaryl derivatives of pnictogen ligands (tpE, E = P (tpp, tptp, or totp), As (tpAs), Sb (tpSb)) with the formulas {[Ag(nim) (tpp)2]DMF} (1), [Ag(nim) (tptp)2] (2), [Ag(nim) (totp)] (3), [Ag(nim) (tpAs)2] (4), and [Ag(nim) (tpSb)3] (5) ((tpp = triphenyphosphine, tptp = tri(p-tolyl)phosphine, totp = tri(o-tolyl)phosphine, tpAs = triphenylarsine, tpSb = triphenylantimony, and DMF = dimethylformamide) were synthesized and characterized by melting point, vibrational spectroscopy (mid-Fourier transform IR), (1)H NMR, UV-visible spectroscopic techniques, and X-ray crystallography. The in vitro cytotoxic activity of 1-5 against human breast adenocarcinoma cancer cell lines: MCF-7 (estrogen receptor (ER) positive) and MDA-MB-231 (ER negative) was determined. The genotoxicity on normal human fetal lung fibroblast cells (MRC-5) caused by 1-5 was evaluated by fluorescence microscopy. The absence of micronucleus in MRC-5 cells confirms the in vitro non toxicity behavior of the compounds. Because of the morphology of the cells, an apoptotic pathway was concluded for the cell death. The apoptotic pathway, especially though the mitochondrion damage, was confirmed by DNA fragmentation, cell cycle arrest, and permeabilization of the mitochondrial membrane tests. The molecular mechanism of action of 1-5 was further studied by (i) the binding affinity of 1-5 toward the calf thymus (CT) DNA, (ii) the inhibitory activity of 1-5 against lipoxygenase (an enzyme that oxidizes polyunsaturated fatty acids to leukotrienes or prostaglandins), and (iii) the catalytic activity of 1-5 on the oxidation of linoleic acid (an acid that partakes in membrane fluidity, membrane enzyme activities, etc.) to hyperoxolinoleic acid by oxygen.

Recent advances on antimony(III/V) compounds with potential activity against tumor cells.

Antimony one of the heavier pnictogens, has been in medical use against microbes and parasites as well. Antimony-based drugs have been prescribed against leishmaniasis since the parasitic transmission of the tropical disease was understood in the beginning of the 20th century. The activity of arsenic against visceral leishmaniasis led to the synthesis of an array of arsenic-containing parasitic agents, among them the less toxic pentavalent antimonials: Stibosan, Neostibosan, and Ureastibamine. Other antimony drugs followed: sodium stibogluconate (Pentostam) and melglumine antimoniate (Glucantim or Glucantime); both continue to be in use today despite their toxic side effects and increasing loss in potency due to the growing resistance of the parasite against antimony. Antimony compounds and their therapeutic potentials are under consideration from many research groups, while a number of early reviews recording advances of antimony biomedical applications are also available. However, there are only few reports on the screening for antitumor potential of antimony compounds. This review focuses upon results obtained on the anti-proliferative activity of antimony compounds in the past years. This survey shows that antimony(III/V) complexes containing various types of ligands such as thiones, thiosemicarbazones, dithiocarbamates, carboxylic acids, or ketones, nitrogen donor ligands, exhibit selectivity against a variety of cancer cells. The role of the ligand type of the complex is elucidated within this review. The complexes and their biological activity are already reported elsewhere. However quantitative structure-activity relationship (QSAR) modeling studies have been carried out and they are reported for the first time here.

New antibacterial, non-genotoxic materials, derived from the functionalization of the anti-thyroid drug methimazole with silver ions

The new silver(I) compound {[AgBr(μ2-S-MMI)(TPP))]2} (1) and the known one [AgCl(TPP)2(MMI)] (2) were obtained by refluxing toluene solutions of silver(I) halide with triphenylphosphine (TPP) and the anti-thyroid drug 2-mercapto-1-methyl-imidazole or methimazole (MMI). The complexes were characterized by m.p., vibrational spectroscopy (mid-FT-IR), (1)H, (31)P-NMR, UV-Vis spectroscopic techniques and X-ray crystallography. The antibacterial effect of 1 and 2 against the bacterial species Pseudomonas aeruginosa (PAO) and Escherichia coli was evaluated. Compound 1 exhibits comparable activity to the corresponding one of the silver nitrate which is an antibacterial drug in use. The in vivo genotoxicity of 1-2 by the mean of Allium cepa test shows no alterations in the mitotic index values due to the absence of chromosomal aberrations. The mechanism of action of the title compounds is evaluated. The DNA binding tests indicate the ability of the complexes 1-2 to modify the activity of the bacteria. The binding constants of 1-2 towards CT-DNA indicate interaction through opening of the hydrogen bonds of DNA. Docking studies on DNA-complexes interactions confirm the binding of both complexes 1-2 in the major groove of the CT-DNA. In conclusion the silver complex 1 is an anti-bacterial and non-genotoxic material, which can be applied to antibacterial drug in the future.

Novel mixed metal Ag(I)-Sb(III)-metallotherapeutics of the NSAIDs, aspirin and salicylic acid: Enhancement of their solubility and bioactivity by using the surfactant CTAB

The already known Ag(I)-Sb(III) compound of the formula {Ag(Ph3Sb)3(NO3)} (1) and two novel mixed metal Ag(I)-Sb(III) metallotherapeutics of the formulae {Ag(Ph3Sb)3(SalH)}(2) and {Ag(Ph3Sb)3(Asp)}(3) (SalH2=salicylic acid, AspH=aspirin or 2-acetylsalicylic acid and Ph3Sb=triphenyl antimony(III)) have been synthesised and characterised by m.p., vibrational spectroscopy (mid-FT-IR), (13)C-,(1)H-NMR, UV-visible (UV-vis) spectroscopic techniques, high resolution mass spectroscopy (HRMS) and X-ray crystallography. Compounds 1,-3 were treated with the surfactant cetyltrimethylammonium bromide (CTAB) in order to enhance their solubility and as a consequence their bioactivity. The resulting micelles a-c were characterised with X-ray powder diffraction (XRPD) analysis, X-ray fluorescence (XRF) spectroscopy, Energy-dispersive X-ray spectroscopy (EDX), conductivity, Thermal gravimetry-differential thermal analysis (TG-DTA), and atomic absorption. Compounds 1-3 and the relevant micelles a-c were evaluated for their in vitro cytotoxic activity against human cancer cell lines: MCF-7 (breast, estrogen receptor (ER) positive), MDA-MB-231 (breast, ER negative) and MRC-5 (normal human fetal lung fibroblast cells) with sulforhodamine B (SRB) colorimetric assay. The results show significant increase in the activity of micelles compared to that of the initial compounds. Moreover, micelles exhibited lower activity against normal cells than tumor cells. The binding affinity of a-c towards the calf thymus (CT)-DNA, lipoxygenase (LOX) and glutathione (GSH) was studied by the fluorescent emission light and UV-vis spectroscopy.

Novel bismuth compounds: synthesis, characterization and biological activity against human adenocarcinoma cells

Five new bismuth(III) halide compounds (BiX3, X = Br or I) of formulae {[BiBr(Me2DTC)2]n} (1), {[BiBr2(Et2DTC)]n} (2), {[BiI2(Me2DTC)]n} (3), {[BiI(Et2DTC)2]n} (4) and {[BiI(μ2-I)(Et2DTC)2]2}n (5) (Me2DTCH = dimethyldithiocarbamate, C3H7NS2 and Et2DTCH = diethyldithiocarbamate, C5H11NS2) were synthesized from the reactions between bismuth(III) bromide (BiBr3) or bismuth(III) iodide (BiI3) with tetramethylthiuram monosulfide (Me4tms), tetramethylthiuram disulfide (Me4tds) or tetraethylthiuram disulfide (Et4tds). The complexes were characterized by melting point, elemental analysis, FT-IR spectroscopy, Raman spectroscopy, 1H, 13C NMR spectroscopy and Thermal Gravimetry-Differential Thermal Analysis (TG-DTA). Moreover, the crystal structures of 1–5 were determined with single crystal X-ray diffraction analysis. The ligands of compounds 1–5 were derived from reduction with concomitant degradation to dithiocarbamates. Complexes 1–4 are polymers, whereas complex 5 is a dimer, built up from monomeric units with square pyramidal (SP) geometry (1, 4 and 5) and pentagonal bipyramidal geometry (2 and 3) around the bismuth center. Complexes 1–5 were evaluated for their in vitro cytotoxic activity against human adenocarcinoma breast (MCF-7) and cervix (HeLa) cells. The toxicity on normal human fetal lung fibroblast cells (MRC-5) is also evaluated. Since estrogen receptors (ERs) are located in MCF-7, in contrast to HeLa cells, the estrogenic effect of 1–5 on MCF-7 cells was studied by means of a methylene blue assay. Hirshfeld surface volumes were analyzed to clarify the nature of the intermolecular interactions. Molecules with lower H-all atoms inter-molecular interactions tend to exhibit higher activity against both MCF-7 and HeLa cells. Structure–activity relationship (SAR) studies were performed for these complexes using 2D topological based disparity analysis. This finding underlines the significance of the halogen atoms in the coordination sphere of the metal ion.