Hydrogels containing water soluble conjugates of silver(I) ions with amino acids, metabolites or natural products for non infectious contact lenses.

The poor handling and hygiene practices of contact lenses are the key reasons for their frequent contamination, and are responsible for developing ocular complications, such as microbial keratitis (MK). Thus there is a strong demand for the development of biomaterials of which contact lenses are made, combined with antimicrobial agents. For this purpose, the known water soluble silver(I) covalent polymers of glycine (GlyH), urea (U) and the salicylic acid (SalH2) of formulae [Ag3(Gly)2NO3]n (AGGLY), [Ag(U)NO3]n (AGU), and dimeric [Ag(salH)]2 (AGSAL) were used. Water solutions of AGGLY, AGU and AGSAL were dispersed in polymeric hydrogels using hydroxyethyl-methacrylate (HEMA) to form the biomaterials pHEMA@AGGLY-2, pHEMA@AGU-2, and pHEMA@AGSAL-2. The biomaterials were characterized by X-ray fluorescence (XRF) spectroscopy, thermogravimetric differential thermal analysis (TG-DTA), differential scanning calorimetry (DTG/DSC), attenuated total reflection spectroscopy (FT-IR-ATR) and single crystal diffraction analysis. The antibacterial activity of AGGLY, AGU, AGSAL, pHEMA@AGGLY-2, pHEMA@AGU-2 and pHEMA@AGSAL-2 was evaluated against the Gram negative species Pseudomonas aeruginosa (P. aeruginosa) and Gram positive ones Staphylococcus epidermidis (S. epidermidis) and Staphylococcus aureus (S. aureus), which mainly colonize in contact lenses. The in vitro toxicity of the biomaterials and their ingredients was evaluated against normal human corneal epithelial cells (HCECs) whereas the in vitro genotoxicity was evaluated by the micronucleus (MN) assay in HCECs. The Artemia salina and Allium cepa models were applied for the evaluation of in vivo toxicity and genotoxicity of the materials. Following our studies, the new biomaterials pHEMA@AGGLY-2, pHEMA@AGU-2, and pHEMA@AGSAL-2 are suggested as efficient candidates for the development of antimicrobial contact lenses.

Organotin derivatives of cholic acid induce apoptosis into breast cancer cells and interfere with mitochondrion; Synthesis, characterization and biological evaluation.

Organotin(IV) derivatives of cholic acid (CAH) with the formulae R3Sn(CA) (R = Ph- (1), n-Bu- (2)) and R2Sn(CA)2 (R = Ph- (3), n-Bu- (4) and Me- (5)) were synthesized. The compounds were characterized in solid state by melting point, FT-IR, 119Sn Mössbauer, X-ray fluorescence (XRF) spectroscopy and in solution by 1H NMR, UV-Vis spectral data and by Electrospray Ionisation Mass spectrometry (ESI-MS), High Resolution Mass spectrometry (HRMS), and atomic absorption analysis. The in vitro bioactivity of 1-5 against human breast adenocarcinoma cancer cells MCF-7 (positive to hormone receptors) and MDA-MB-231 (negative to hormone receptors) reveal that triorganotin derivatives 1-2 exhibit significantly stronger activity than the corresponding diorganotin ones. Compound 5 is inactive against both cell lines at the concentrations tested. Triorganotins 1-2 inhibit selectively MCF-7 than MDA-MB-231 cells, suggesting hormone mimetic behavior of them. Organotins 1-4 inhibit both cancerous cell lines, stronger than cisplatin which rise up to 55-fold against MCF-7 and 170-fold against MDA-MB-231. The in vitro toxicity of 1-4 was evaluated on normal human fetal lung fibroblast cells (MRC-5), while their genotoxicity in vitro by micronucleus assay (MN). Moreover, the in vivo toxicity of 1-4 was tested by Artemia salina assay and their in vivo genotoxicity with Allium cepa test. The mechanism of action of 1-4 against MCF-7 was clarified in vitro by the means of cell morphology studies, cell cycle arrest, Acridine Orange/Ethidium Bromide (AO/EB) Staining, mitochondrial membrane permeabilization test and by their binding affinity toward the calf thymus (CT) DNA.

Tetracycline Water Soluble Formulations with Enhanced Antimicrobial Activity.

The negligible water solubility of tetracycline (TC), a well-known antibiotic of clinical use, is the major disadvantage for its oral administration. With the aim to improve the water solubility of TC, the micelles of formulae SLS@TC and CTAB@TC (SLS = sodium lauryl sulphate and CTAB = cetrimonium bromide) were synthesized. The micelles SLS@TC and CTAB@TC were characterized by melting point (m.p.), thermogravimetric differential thermal analysis (TG-DTA), differential scanning calorimetry (DTG/DSC), attenuated total reflection spectroscopy (FT-IR-ATR), ultra-violet visible (UV/vis) spectroscopy, proton nucleus magnetic resonance (1H-NMR) spectroscopy, and the ultrasonically-induced biregringence technique. The antimicrobial activity of SLS@TC and CTAB@TC was evaluated, by means of minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and inhibition zone (IZ), against the Gram negative bacterial strains Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli) and the Gram positive ones of the genus of Staphylococcus epidermidis (S. epidermidis) and Staphylococcus aureus (S. aureus). Generally, both micelles show better activity than that of TC against the microbial strains tested. Thus, the MIC value of CTAB@TC is 550-fold higher than that of free TC against S. epidermidis. Despite the stronger activity of CTAB@TC than SLS@TC against both Gram negative and Gram positive microbes, SLS@TC is classified as a bactericidal agent (in that it eliminates 99.9% of the microbes), in contrast to CTAB@TC, which is bacteriostatic one (inhibits, but does not kill the organisms). The toxicity of SLS@TC and CTAB@TC was evaluated against human corneal eukaryotic cells (HCECs). Moreover, SLS@TC and CTAB@TC exhibit low in vivo toxicity against Artemia salina, even at concentrations up to threefold higher than those of their MICmax. Therefore, SLS@TC and CTAB@TC can be candidates for the development of new antibiotics.

Ciprofloxacin conjugated to diphenyltin(IV): a novel formulation with enhanced antimicrobial activity.

The metalloantibiotic of formula Ph2Sn(CIP)2 (CIPTIN) (HCIP = ciprofloxacin) was synthesized by reacting ciprofloxacin hydrochloride (HCIP·HCl) (an antibiotic in clinical use) with diphenyltin dichloride (Ph2SnCl2DPTD). The complex was characterized in the solid state by melting point, FT-IR, X-ray Powder Diffraction (XRPD) analysis, 119Sn Mössbauer spectroscopy, X-ray Fluorescence (XRF) spectroscopy, and Thermogravimetry/Differential Thermal Analysis (TG-DTA) and in solution by UV-Vis, 1H NMR spectroscopic techniques and Electrospray Ionisation Mass Spectrometry (ESI-MS). The crystal structure of CIPTIN and its processor HCIP was also determined by X-ray crystallography. The antibacterial activity of CIPTIN, HCIP·HCl, HCIP and DPTD was evaluated against the bacterial species Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis), by the means of Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Inhibition Zones (IZs). CIPTIN shows lower MIC values than those of HCIP·HCl (up to 4.2-fold), HCIP (up to 2.7-fold) or DPTD (>135-fold), towards the tested microbes. CIPTIN is classified into bactericidal agents according to MBC/MIC values. The developing IZs are 40.8 ± 1.5, 34.0 ± 0.8, 36.0 ± 1.1 and 42.7 ± 0.8 mm, respectively which classify the microbes P. aeruginosa, E. coli, S. aureus and S. epidermidis to susceptible ones to CIPTIN. These IZs are greater than the corresponding ones of HCIP·HCl by 1.1 to 1.5-fold against both the tested Gram negative and Gram positive bacteria. CIPTIN eradicates the biofilm of P. aeruginosa and S. aureus more efficiently than HCIP·HCl and HCIP. The in vitro toxicity and genotoxicity of CIPTIN were tested against human skin keratinocyte cells (HaCaT) (IC50 = 2.33 µM). CIPTIN exhibits 2 to 9-fold lower MIC values than its IC50 against HaCaT, while its genotoxic effect determined by micronucleus assay is equivalent to the corresponding ones of HCIP·HCl or HCIP.

pHEMA@AGMNA-1: A novel material for the development of antibacterial contact lens.

The Metal Organic Framework (MOF) of formula {[Ag6(µ3-HMNA)4(µ3-MNA)2]2-·[(Et3NH)+]2·(DMSO)2·(H2O)} (AGMNA), a known efficient antimicrobial compound which contains the anti-metabolite, 2-thio-nicotinic acid (H2MNA), was incorporated in polymer hydrogels using, hydroxyethyl-methacrylate (HEMA). The material pHEMA@AGMNA-1 was characterized by X-ray fluorescence (XRF) spectroscopy, X-ray powder diffraction analysis (XRPD), Scanning Electron Microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDX), Thermogravimetric Differential Thermal Analysis (TG-DTA), Differential Scanning Calorimetry (DTG/DSC), attenuated total reflection spectroscopy (FT-IR-ATR) and Ultrasonic Imaging. The antimicrobial capacity of pHEMA@AGMNA-1 was evaluated against the Gram negative bacterial strain Pseudomonas aeruginosa and the Gram positive ones of the genus of Staphylococcus epidermidis and Staphylococcus aureus, which are the etiology of the microbial keratitis. The % bacterial viability of P. aeruginosa, S. epidermidis and S. aureus upon their incubation with pHEMA@AGMNA-1 discs is significantly low (0.4 ± 0.1%, 1.5 ± 0.4% and 7.7 ± 0.5% respectively). The inhibition zones (IZ) caused by pHEMA@AGMNA-1 discs against P. aeruginosa, S. epidermidis and S. aureus are 14.0 ± 1.1, 11.3 ± 1.3 and 11.8 ± 1.8 mm respectively. Furthermore, pHEMA@AGMNA-1 exhibits low toxicity. Thus, pHEMA@AGMNA-1 might be an efficient candidate for the development of antimicrobial active contact lenses.

Antiproliferative activity and apoptosis induction, of organo-antimony(III)-copper(I) conjugates, against human breast cancer cells.

Three known organo-antimony(III)-copper(I), mixed-metal small bioactive molecules (SBAMs) of formula [Cu(tpSb)3Cl] (1), [Cu2(tpSb)4Br2] (2) and [Cu2(tpSb)4I2] (3) (tpSb = triphenylstibine) were used for the clarification of their antiproliferative activity against human breast cancer cells: MCF-7 (hormone-dependent cells) and MDA-MB-231 (hormone-independent cells). The in vitro toxicity of 1-3 was studied against normal human foetal lung fibroblast cells (MRC-5). The genotoxicity of 1-3 was determined by the presence of micronucleus. The type of the cell death caused by 1-3 was determined using cell cycle arrest. The molecular mechanism of action of 1-3 was defined by their binding affinity towards CT-DNA (calf thymus DNA) using UV spectroscopy and viscosity measurements. Docking studies depict the interactions between 1-3 and DNA. Computations were also employed in order to rationalize the activity of these compounds. This is based on the contribution of metal aromaticity in the case of compounds 2 and 3 where the short Cu···Cu distance (2.7724(6) (2) and 2.7251(11) (3) Ǻ, respectively) suggests d10-d10 interaction between metal centres. The known small bioactive molecules of formula [Cu(tpSb)3Cl] (1), [Cu2(tpSb)4Br2] (2) and [Cu2(tpSb)4I2] (3) (tpSb = triphenylstibine) were used for the clarification of their antiproliferative activity against human breast cancer cells: MCF-7 (hormone-dependent (HD) cells) and MDA-MB-231 (hormone-independent (HI) cells).

An Efficient Disinfectant, Composite Material {SLS@[Zn3(CitH)2]} as Ingredient for Development of Sterilized and Non Infectious Contact Lens.

The [Zn3(CitH)2] (1) (CitH4= citric acid), was dispersed in sodium lauryl sulphate (SLS) to form the micelle of SLS@[Zn3(CitH)2] (2). This material 2 was incorporated in hydrogel made by hydroxyethyl-methacrylate (HEMA), an ingredient of contact lenses, toward the formation of pHEMA@(SLS@[Zn3(CitH)2]) (3). Samples of 1 and 2 were characterized by UV-Vis, 1H-NMR, FT-IR, FT-Raman, single crystal X-ray crystallography, X-ray fluorescence analysis, atomic absorption and TG/DTA/DSC. The antibacterial activity of 1-3 as well as of SLS against Gram-positive (Staphylococcus epidermidis (St. epidermidis) and Staphylococcus aureus (St. aureus)) and Gram-negative (Pseudomonas aeruginosa (PAO1), and Escherichia coli (E. coli)) bacteria was evaluated by the means of minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and inhibitory zone (IZ). 2 showed 10 to 20-fold higher activity than 1 against the bacteria tested. Moreover the 3 decreases the abundance of Gram-positive microbes up to 30% (St. aureus) and up to 20% (PAO1) the Gram-negative ones. The noteworthy antimicrobial activity of the obtained composite 3 suggests an effective antimicrobial additive for infection-free contact lenses.

A water-soluble silver(I) formulation as an effective disinfectant of contact lenses cases.

The antibacterial effect of the already known water-soluble compound {[Ag6(µ3-Hmna)4(µ3-mna)2]2-·[(Et3NH)+]2·(DMSO)2·(H2O)} (AGMNA) (H2mna = 2­mercapto­nicotinic acid) was evaluated by the mean of the Minimum Inhibitory Concentration (MIC), the Minimum Bactericidal Concentration (MBC) and the Inhibitory Zone (IZ), against the bacterial strains Pseudomonas aeruginosa (PAO1) and Staphylococcus aureus (St. aureus) which settle in the cornea, in bacterial keratitis. The MICs' of AGMNA against PAO1 and St. aureus were 25.7 ±â€¯2.4 µM and 42.0 ±â€¯0.3 µM respectively. Τhe Biofilm Elimination Concentration (ΒΕC) was used to evaluate the influence of AGMNA on the formation of biofilm of PAO1. AGMNA exhibits stronger antimicrobial activity than that of H2mna or AgNO3. The toxicity of AGMNA was examined against normal human corneal epithelial cells (HCET cells) and by micronucleus (MN) assay in HCET cells. Thus, the IC50 value of AGMNA, towards HCET cells is higher than 120 µΜ, while its effect on MN frequency, of HCET cells, is meaningless, when they are treated with it at 120 µΜ, suggesting no in vitro genotoxicity. The Mitotic Index (MI), Chromosomal Aberrations (CA) and Nuclear Abnormalities (NA) analyses of Allium cepa reveal insignificant variations between treated and untreated ones indicating no in vivo genotoxicity.

Silver ciprofloxacin (CIPAG): a successful combination of chemically modified antibiotic in inorganic-organic hybrid.

The new silver(I) ionic, water soluble, compound {[Ag(CIPH)2]NO3∙0.75MeOH∙1.2H2O} (CIPAG) was obtained by reacting silver(I) nitrate with the antibiotic ciprofloxacin (CIPH). The complex was characterized by m.p., mid-FT-IR, 1H-NMR, UV-Vis spectroscopic techniques. The crystal structures of both CIPAG and the hexahydrated neutral free drug {[CIPH]∙6(H2O)} (2) were characterized by X-ray crystallography. Two neutral ligands are datively bonded to the metal ion through the piperidinic nitrogen atoms forming a cationic {[Ag(CIPH)2]+} counter part which is neutralized by a nitrate group. The antibacterial effect of CIPAG and the commercially available hydrochloric salt of the antibiotic ({[CIPH 2+ ]∙Cl - } (3)) were tested against the bacterial species Pseudomonas aeruginosa (PAO1), Staphylococcus epidermidis (St. epidermidis) and Staphylococcus aureus (St. aureus) by the mean of minimum inhibitory concentration, minimum bactericidal concentration and their inhibitory zone (IZ). The influence of CIPAG and 3 against the formation of biofilm of PAO1 or St. aureus was also evaluated by mean of biofilm elimination concentration. The IZ caused by CIPAG which has been loaded in poly-hydroxyethylmethacrylate, is determined. The genotoxicity of CIPAG and 3 is tested in vitro against normal human corneal epithelial cells (HCET cells), by the presence of micronucleus in HCET cells and in vivo by mean of Allium cepa test.

Innovative material containing the natural product curcumin, with enhanced antimicrobial properties for active packaging.

Curcumin (Curc) reacts with zinc di­iodine (ZnI2) in 2:1molar ratio in the presence of an excess of a base triethylamine ((CH3CH2)3N) in methanol (CH3OH) solution towards the amorphous solid material of formula [ZnI2(Curc)2] (1). The complex was characterized by melting point (m.p.), Fourier Transform-Infra Red (FT-IR) and Nuclear Magnetic Resonance of hydrogen nucleus (1H NMR) spectroscopy. The formula of 1 was determined by X-ray fluorescence (XRF) analysis. The retention of the structure in solution was confirmed by 1H NMR spectroscopy. The antimicrobial activity of the complex has been studied against the bacteria Pseudomonas aeruginosa (PAO1). The Minimum Inhibitory Concentrations (MIC) of the compounds 1 and Curc against P. aeruginosa (PAO1) are: 71.3µΜ (75.3µg/mL) for [ZnI2(Curc)2] and 339µM (125µg/mL) for Curc, respectively. Moreover, the antimicrobial activity of the new material which was diffused in polystyrene against biofilm formed by PAO1 was also calculated.

Chloro(triphenylphosphine)gold(I) a forefront reagent in gold chemistry as apoptotic agent for cancer cells.

The antiproliferative activity of the gold complex [Au(tpp)Cl] (1) (tpp=triphenyphosphine) against human breast adenocarcinoma cells (MCF-7) and normal human fetal lung fibroblast cells (MRC-5) was investigated. The compound exhibits stronger activity against MCF-7 cells than cisplatin. The apoptotic pathway, especially though the mitochondrion damage was concluded by cell cycle arrest, flow cytometry using Annexin V-Fluorescein IsoThioCyanate (FITC) and Propidium Iodide (PI) as indicators, assays and permeabilization of the mitochondrial membrane tests. The molecular mechanism of action of 1 was further studied by: (i) its catalytic activity on the oxidation of linoleic acid (an acid that partakes in membrane fluidity) to hyperoxolinoleic acid by oxygen and (ii) its binding affinity towards the calf thymus (CT) DNA. Since the deactivation of cisplatin by glutathione (GSH), is related with the development of cell resistance, the reaction of 1 with GSH was investigated by UV absorption spectroscopy. The absence of micronucleus in cells confirms that the complex has no in vitro toxicity. The in vivo genotoxicity caused by 1 was evaluated by Allium cepa test.

Structural, photolysis and biological studies of novel mixed metal Cu(I)-Sb(III) mixed ligand complexes.

Direct reaction of copper(I) halides with triphenylstibine (tpSb) and 2-mercapto-thiazolidine (tzdtH) in 1:1:1 molar ratio, results in the formation of the [CuX(µ2-S)-tzdtH)(tpSb)]2 (X=Cl (1), Br (2) and I (3)) complexes. The complexes have been characterized by melting point, FT-IR, UV-vis, (1)H NMR spectroscopic data and X-ray crystallography. Complexes 1-3 are di-nuclear and they are the first examples of mixed metals (CuSb), mixed ligand (thioamide, stibine and halogen) containing complexes. Two µ2-S (1-3) atoms bridge the two copper(I) ions with tetrahedral geometry. The coordination sphere around copper atoms is completed by one Sb from tpSb and one halogen (chlorine, bromine or iodine) atom. Intermolecular via N-H⋯X (Cl (1) and Br (2)) interactions stabilized the assembly. The short coppercopper bond distances of 3.103 (1), 3.061 (2) and 3.110, 3.108 (3) Ǻ found in 1-3 indicates d(10)-d(10) interaction between metal centers. The complexes exhibit high photo-sensitivity to UVB light. The complexes 1-3 and the already known [Cu(µ2-I)(tpSb)2]2 (4) were tested for their in vitro cytotoxic activity against human cancer cell lines: MCF-7 (breast, estrogen receptor (ER) positive), MDA-MB-231 (breast, estrogen receptor (ER) negative) and MRC-5 (normal human fetal lung fibroblast cells) with sulforhodamine B (SRB) colorimetric assay. Since estrogen receptors (ERs) are located in MCF-7, in contrast to MDA-MB-231 cells, the estrogenic effect of 1-4 on MCF-7 cells was studied by the mean of methylene blue assay. Compound 4 exhibits the highest estrogenic effect. None of 1-4 exceeds the activity of cisplatin against MCF-7 cells, but they are more active than cisplatin towards MDA-MB-231 cells. UVB light increases the effectiveness of complexes on MCF-7 cells which in the case of 4 is up to 28% higher than the corresponding initial complex (without irradiation).

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.

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.

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.

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.

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.

A novel silver iodide metalo-drug: experimental and computational modelling assessment of its interaction with intracellular DNA, lipoxygenase and glutathione.

The new mixed ligand silver(I) complex of formula [AgI(TPP)2(MBZT)] (1) was obtained by reacting 2-mercapto-benzothiazole (MBZT) with triphenylphosphine (TPP). The complex was characterized by m.p., vibrational spectroscopy (FT-IR), (1)H NMR, UV-vis, ESI-MS spectroscopic techniques and its structure was confirmed by X-ray crystallography. Mixed ligand complexes of silver(I) iodide with thiones and phosphines are very rare in the literature and to the best of our knowledge compound 1 is the first of this kind exhibiting significant biological effects. Complex 1 was evaluated for its in vitro cytotoxic activity (cell viability) under irradiation with UV light and without irradiation against human cancer cell lines: MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), Caki-1 (renal), A549 (lung), OAW-42 (ovarian), HeLa (cervical) and additionally against 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 SRB assay. The results showed that 1 mediates a strong cytotoxic response to the tested normal and cancer cell lines. It exhibits equal activity against MDA-MB-231 cells where estrogen receptors (ERs) are devoid with the one against MCF-7 where ERs are present. Molecular docking studies have shown that 1 is docked in the different pocket than that of the ERs modulators. The binding affinity of 1 towards the intracellular molecules DNA and lipoxygenase (LOX) was studied for the evaluation of the mechanism of its cytostasis. The binding constant (Kb) of 1 towards CT-DNA was calculated by UV-Vis and fluorescent spectra suggesting intercalation or electrostatic interactions of 1 into DNA. Docking studies on DNA-complex interactions confirm the binding of 1. Moreover, the influence of complex 1 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. In addition, since the deactivation of cisplatin caused by glutathione, seems to be an important determinant of its cytotoxic effects, the reaction of 1 with glutathione (GSH) was investigated by UV-absorption spectroscopy.

Novel metallo-therapeutics of the NSAID naproxen. Interaction with intracellular components that leads the cells to apoptosis.

Two new mixed ligand-silver(I) complexes of the anti-inflammatory drug naproxen (naprH) and triphenylphosphine (tpp) or tri(p-tolyl)phosphine (tptp) of formulae {[Ag(tpp)3(napr)](H2O)} (1) and [Ag(tptp)2(napr)] (2) have been synthesized and characterized by m.p., vibrational spectroscopy (mid-FT-IR), Raman, (1)H-NMR, UV-Vis, ESI-MS spectroscopic techniques and X-ray crystallography. The complexes show high photo-sensitivity to UVC light. Photolysis of 1-2 was studied and the results showed monotonic degradation of the complexes with simultaneous triarylphosphine oxide formation. The complexes 1-2 were tested for their antiproliferative activity against human breast adenocarcinoma (MCF-7) cells. Complexes 1-2 were more active than cisplatin against cells. UVC light increases the effectiveness of complexes 1-2 on MCF-7 cells by 13% and 38% respectively. Due to the morphology of the MCF-7 cells, which were incubated with the complexes 1-2, the cell death was ascribed to apoptosis. Electrophoresis to genomic DNA of MCF-7 cells confirmed the apoptosis through DNA fragmentation. The binding affinity of 1-2 towards the intracellular molecules CT-DNA and lipoxygenase (LOX) was studied for the evaluation of the mechanism of cell death. Thus, the binding constants (K(b)) of 1-2 towards CT-DNA calculated by UV-Vis spectra are 32.8 ± 8.5 × 10(4) (1) and 4.7 ± 1.8 × 10(4) (2) M(-1), respectively. Changes in fluorescent emission light of ethidium bromide (EB) in the presence of DNA suggest intercalation or electrostatic interactions into DNA of both complexes 1-2 in the minor groove. The corresponding apparent binding constants (K(app)) of 1-2 towards CT-DNA calculated through fluorescence spectra are 2.9 ± 0.3 × 10(4) (1) and 1.6 ± 0.4 × 10(4) (2) M(-1) respectively. Docking studies on DNA-complexes interactions show the binding of 1 in the major groove and the corresponding one of 2 in the minor one. Moreover, the influence of complexes 1-2 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. Only 1 inhibits lipoxygenase activity (IC50 = 5.1 (1), >30 (2) µM).

Synthesis, antiradical activity and in vitro cytotoxicity of novel organotin complexes based on 2,6-di-tert-butyl-4-mercaptophenol.

A series of organotin complexes with Sn-S bonds of formulae Me2Sn(SR)2 (1); Et2Sn(SR)2 (2); (n-Bu)2Sn(SR)2 (3); Ph2Sn(SR)2 (4); R2Sn(SR)2 (5); Me3SnSR (6); Ph3SnSR (7) (R = 3,5-di-tert-butyl-4-hydroxyphenyl) were synthesized and characterized by elemental analysis, (1)H, (13)C NMR, and IR. The crystal structures of compounds 1, 4, 5, and 7 were determined by X-ray diffraction analysis. The tetrahedral geometry around the Sn center in the monocrystals of 1, 4, 5, and 7 was confirmed by X-ray crystallography. The high radical scavenging activity of the complexes was confirmed spectrophotometrically in a DPPH-test. The binding affinity of 1-7 and the starting R2SnCl2 (8) towards tubulin through their interaction with SH groups of proteins was studied. It was found that the hindered organotin complexes could interact with the colchicine site of tubulin, which makes them promising antimitotic drugs. Compounds 1-8 were tested for their in vitro cytotoxicity against human breast (MCF-7) and human cervix (HeLa) adenocarcinoma cells. Complexes 1-8 were also tested against normal human fetal lung fibroblast cells (MRC-5). Complexes 2-4 and 8 exhibit significantly lower cytostatic activity against the normal MRC-5 cell line compared to the tumor cell lines MCF-7 and HeLa used. A high activity against both cell lines 250 nM (MCF-7) and 160 nM (HeLa) was determined for the triphenyltin complex 7 while the introduction of hindered phenol groups decreases the cytotoxicity of the complexes against normal cells.