Human Fetal Lung Fibroblast Cells Research Articles

Structural architectures and biological properties of main group bismuth(III) iodide complexes with heterocyclic thioamides

A series of mononuclear, dinuclear and polynuclear bismuth(III) iodide complexes (1–5) bearing heterocyclic thioamide ligands, 2-mercapto-3,4,5,6-tetrahydro-pyrimidine (tHPMT), 2-mercapto-benzimidazole (MBZIM), 2-mercapto-1-methylimidazole (MMI), 2-mercaptobenzothiazole (MBZT) and 2-mercaptopyridine (PYT), have been synthesized and characterized by melting point, elemental analysis, FT-IR spectroscopy, Raman spectroscopy, 1H, 13C NMR spectroscopy, UV–Vis spectroscopy and Thermal Gravimetry-Differential Thermal Analysis (TG-DTA). Moreover, the crystal structures of 1–5 have been also determined with single crystal X-ray diffraction analysis. The use of the above mentioned heterocyclic thioamide ligands have allowed synthesis of the first examples of bismuth(III) iodide thioamide complexes. {[BiI3(tHPMT)3]} (1) is the first structural example of a neutral mononuclear bismuth(III) iodide complex with octahedral geometry around the bismuth(III) ion with meridional conformation. {[BiI2(µ2-I)(MBZIM)2]2} (2) is the first example of a dinuclear bismuth(III) iodide complex with octahedral geometry around the bismuth(III) ion with trans-S/cis-I arrangement. {[BiI(µ2-I)2(MMI)]n} (3) and {[BiI(µ2-I)2(MBZT)]n·CH3OH} (4) are the first examples of the polynuclear bismuth(III) iodide complexes with octahedral geometry around the bismuth(III) ions. The ligand molecules are coordinated via the thione sulfur atoms in both complexes but in complex 3, ligand molecules are trans to each other in polymeric chain while, in complex 4, ligand molecules are cis to each other in polymeric chain. {[BiI(µ2-S,N-PYT)2]n} (5) is the first example of a polynuclear bismuth(III) iodide complex with pentagonal bipyramidal geometry around the bismuth(III) ions. The seven coordinate bismuth(III) atom has a N2S4I-donor set consisting of one iodine atom and two chelating and bridging μ2-S,N (η2-S:η1-N) pyridine-2-thionate anions.Complexes 1–5 were evaluated for their in vitro cytotoxic activity against human adenocarcinoma cervix (HeLa) and breast (MCF-7) cancer cells. The toxicity of the complexes was studied against human fetal lung fibroblast cells (MRC-5). The influence of 1–5, upon the catalytic peroxidation of the linoleic acid by the enzyme lipoxygenase (LOX), was evaluated experimentally.

A Multi-Biochemical and In Silico Study on Anti-Enzymatic Actions of Pyroglutamic Acid against PDE-5, ACE, and Urease Using Various Analytical Techniques: Unexplored Pharmacological Properties and Cytotoxicity Evaluation.

In the current study, pyroglutamic acid (pGlu), a natural amino acid derivative, has efficiently inhibited the catalytic activities of three important enzymes, namely: Human recombinant phosphodiesterase-5A1 (PDE5A1), human angiotensin-converting enzyme (ACE), and urease. These enzymes were reported to be associated with several important clinical conditions in humans. Radioactivity-based assay, spectrophotometric-based assay, and an Electrospray Ionization-Mass Spectrometry-based method were employed to ascertain the inhibitory actions of pGlu against PDE5A1, ACE, and urease, respectively. The results unveiled that pGlu potently suppressed the activity of PDE5A1 (half-maximal inhibitory concentration; IC50 = 5.23 µM) compared with that of standard drug sildenafil citrate (IC50 = 7.14 µM). Moreover, pGlu at a concentration of 20 µg/mL was found to efficiently inhibit human ACE with 98.2% inhibition compared with that of standard captopril (99.6%; 20 µg/mL). The urease-catalyzed reaction was also remarkably inactivated by pGlu and standard acetohydroxamic acid with IC50 values of 1.8 and 3.9 µM, respectively. Remarkably, the outcome of in vitro cytotoxicity assay did not reveal any significant cytotoxic properties of pGlu against human cervical carcinoma cells and normal human fetal lung fibroblast cells. In addition to in vitro assays, molecular docking analyses were performed to corroborate the outcomes of in vitro results with predicted structure–activity relationships. In conclusion, pGlu could be presented as a natural and multifunctional agent with promising applications in the treatment of some ailments connected with the above-mentioned anti-enzymatic properties.

Synthesis, characterization and biological evaluation of novel antimony(III) iodide complexes with tetramethylthiourea and N-ethylthiourea

Novel trivalent antimony(III) complexes with tetramethylthiourea (TMTU) and N-ethylthiourea (NETU) were synthesized by the reaction of antimony(III) iodide (SbI3). Antimony(III) iodide complexes of formulae {[SbI2(µ2-I)(TMTU)2]2} (1) and {[(NETU)SbI2(µ2-I)2(µ2-S-NETU)SbI2(NETU)]} (2) were characterized by spectroscopic techniques (FT-IR, FT-Raman, 1H and 13C NMR), TG-DTA analysis and X-ray diffraction (XRD) analysis. Single-crystal X-ray diffraction studies showed that the complexes existed as doubly bridged (1) and triply bridged (2) dimers. Crystal structure of the ligand N-ethylthiourea was also determined with single crystal X-ray diffraction analysis.Complexes 1 and 2 were evaluated for their in vitro cytotoxic activity against human adenocarcinoma cells HeLa (cervix). The toxicity of 1 and 2 was evaluated on normal human fetal lung fibroblast cells (MRC-5). Both complexes showed selectivity against the cancerous, than normal cells. The influence of 1 and 2, on the catalytic peroxidation of the linoleic acid by the enzyme lipoxygenase (LOX) was determined experimentally and theoretically. The complexes 1 and 2 exhibited higher activity than free ligands against LOX. The in vitro antibacterial activities of free ligands and their antimony(III) iodide complexes 1 and 2 were tested against two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) and two Gram-positive (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212) bacteria. The complexes 1 and 2 were much more effective in terms of antimicrobial activity compared to the free ligands.

Synthesis, characterization and cytotoxic activity of organoruthenium(II)-halido complexes with 5-chloro-1H-benzimidazole-2-carboxylic acid

Three new ruthenium(II)-arene halido complexes, [(η6-p-cymene) RuX(L)] (1–3), were synthesized in a reaction of [(η6-p-cymene)RuX2]2 with 5-chloro-1H-benzimidazole-2-carboxylic acid (HL) in ethanol (X– = Cl– (1), Br– (2), I– (3)). The complexes were characterized by elemental analysis, mass spectrometry, IR, 1H and 13C NMR spectroscopy. The cytotoxic activity of the ligand precursor and its ruthenium complexes was tested by MTT assay in human cancer cell lines: lung adenocarcinoma (A549), myelogenous leukemia (K562) as well as in one normal human fetal lung fibroblast cell line (MRC-5). The results show that ruthenium(II)-arene complexes possess enhanced cytotoxicity when compared to HL in the range of concentrations up to 300 µM. In terms of halido ligand substitution, cytotoxic activity toward A549 and K562 cell lines in 1–3 serie significantly increased (e.g., IC50 values for K562: 1: 205.76 µM; 2: 174.77 µM; 3: 83.97 µM). All studied compounds were found to be ineffective toward MRC-5. Hydrolysis of 1–3 was followed by UV-vis spectroscopy at 25 °C, revealing ligand-substitution reactions at the Ru(II) center. Compounds 2 and 3 underwent rapid hydrolysis ranging from a few minutes for the aquation to ca. 20 min, confirming typical Ru-arene behavior in aqueous solutions.

The periodic table of urea derivative: small molecules of zinc(II) and nickel(II) of diverse antimicrobial and antiproliferative applications.

Two complexes of Zn(II) and Ni(II) ions with the urea derivative, 2-benzimidazolyl-urea (BZIMU), of formulae [ZnBZIMU)2(H2O)](NO3)2 (1) and [Ni(BZIMU)2(CH3CH2OH)2](NO3)2 (2) were synthesized and characterized by their melting point, elemental analysis, spectroscopic techniques (FTIR, UV-Vis and 1H-NMR), High-resolution mass spectroscopy (HRMS), molar conductivity and thermogravimetric analysis. The crystal structures of 1-2 were determined by X-ray diffraction analysis. The antiproliferative activity of 1-2 was tested in vitro against human adenocarcinoma cell lines: cervix (HeLa) and breast (MCF-7). Their toxicity was surveyed against normal human fetal lung fibroblast cells (MRC-5). The bioactivity mechanism of 1-2 and their related analogues of copper and silver metallodrugs are rationalized by the means of computations. The antimicrobial activity of 1-2 against Escherichia coli (E. coli) is also evaluated. The complexes [ZnBZIMU)2(H2O)](NO3)2 (1) and [Ni(BZIMU)2(CH3CH2OH)2](NO3)2 (2) (BZIMU= 2-Benzimidazolyl-urea), were tested in vitro against HeLa and MCF-7 cells. Their toxicity was surveyed against normal MRC-5 cells. The association of the microbiota with the antiproliferative activity of 1-2 was investigated against Escherichia coli.

HPLC-DAD-SPE-NMR isolation of tetracyclic spiro-alkaloids with antiplasmodial activity from the seeds of Erythrina latissima

Seven tetracyclic spiro-alkaloids, i.e. glucoerysodine (1), erysodine (2), epi-erythratidine (3), erysovine (4), erythratidine (5), erysotrine (6) and erythraline (7) were isolated from the seeds of Erythrina latissima by means of conventional separation methods and HPLC-DAD-SPE-NMR. Their structures were elucidated by spectroscopic means. This is the first report on the isolation of compounds 3, 5 and 6 from this plant. Antiplasmodial activity against the chloroquine-resistant strain Plasmodium falciparum K1 and cytotoxicity against MRC-5 cells (human fetal lung fibroblast cells) was assessed in vitro. Erysodine (2) and erysovine (4) showed moderate activity (IC50 6.53 µM and 4.05 µM, respectively), compared with the standard chloroquine (IC50 = 0.14 µM). No cytotoxicity was observed in a concentration up to 64.0 µM.

Bismuth(III) bromide-thioamide complexes: synthesis, characterization and cytotoxic properties

AbstractNew bismuth(III) bromine compounds of the heterocyclic thioamides were prepared and structurally characterized. The reaction of heterocyclic thioamides with bismuth(III) bromide resulted in the formation of the {[BiBr2(μ2-Br)(MMI)2]2·CH3COCH3·H2O} (1), {[BiBr2(MBZIM)4]·Br·2H2O} (2), {[BiBr2(μ2-Br)(tHPMT)2]2·CH3CN} (3), {[BiBr2(μ2-Br)(PYT)2]2·CH3CN} (4) and {[BiBr2(μ2-Br)(MBZT)2]22CH3OH} (5) complexes (MMI: 2-mercapto-1-methylimidazole, MBZIM: 2-mercaptobenzimidazole, tHPMT: 2-mercapto-3,4,5,6-tetrahydro-pyrimidine, PYT: 2-mercaptopyridine and MBZT: 2-mercaptobenzothiazole). The complexes1–5were characterized by melting point (m.p.), elemental analysis (e.a.), molar conductivity, Fourier-transform infrared (FT-IR), Fourier-transform Raman (FT-Raman), nuclear magnetic resonance (1H and13CNMR) spectroscopy, UV-Vis spectroscopy and thermogravimetric-differential thermal analysis (TG-DTA). The molecular structures of1–5were determined by single-crystal X-ray diffraction. Complex2is a first ionic monomuclear octahedral bismuth(III) bromide, while the complexes1,3–5are the first examples of dinuclear bismuth(III) bromide derivatives. Complexes1–5were evaluated in terms of theirin vitrocytotoxic activity against human adenocarcinoma breast (MCF-7) and cervix (HeLa) cells. The toxicity on normal human fetal lung fibroblast cells (MRC-5) was also evaluated. Moreover, the complexes1–5and free heterocyclic thioamide ligands were studied upon the catalytic peroxidation of the linoleic acid by the enzyme lipoxygenase (LOX).

In Vitro Study of Multi-Therapeutic Properties of Thymus bovei Benth. Essential Oil and Its Main Component for Promoting Their Use in Clinical Practice

Thymus bovei Benth. (TB) is an important plant in the traditional medicine of the Mediterranean region. This study investigates the health-promoting properties of TB essential oil (TB-EO) for its possible use in clinical practice with regards to its cytotoxic, anti-herpes simplex virus type 2 (HSV-2), and antihypertensive (through inhibition of human angiotensin-converting enzyme; ACE) properties. The phytochemical profile of EO (99.9%) was analyzed by Gas Chromatography with Flame-Ionization Detection (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS). In this study, all biological methods were performed at the level of in vitro studies. The results showed that TB-EO exerted remarked cytotoxic properties against human cervical carcinoma cells, colon cancer cells, and lung adenocarcinoma cells with the half-maximal inhibitory concentration (IC50) values of 7.22, 9.30, and 8.62 µg/mL, respectively, in comparison with that of standard anticancer drug cisplatin with IC50 values of 4.24, 5.21, and 5.43 µg/mL, respectively. Fascinatingly, TB-EO showed very weak cytotoxicity on the healthy human fetal lung fibroblast cells with an IC50 value of 118.34 µg/mL compared with that of cisplatin (IC50 = 10.08 µg/mL). TB-EO, its main component geraniol, TB-EO combined with acyclovir (ACV) along with standard ACV, have displayed pronounced inhibitory properties against the replication of HSV-2 with the half-maximal effective concentration (EC50) values of 2.13, 1.92, 0.81 and 1.94 µg/mL, respectively, with corresponding selectivity indices (SI) 98.59, 109.38, 259.26 and 108.25, respectively. TB-EO and geraniol at a concentration of 15 µg/mL showed prominent inhibitory activities against ACE with % of inhibition 95.4% and 92.2%, respectively, compared with that of standard inhibitor captopril (99.8%; 15 µg/mL). Molecular docking studies were performed to unveil the mechanism of action of geraniol as well as structural parameters necessary for anti-HSV-2 activity (through the inhibition of HSV-2 protease) and ACE inhibition. This is the first report on the chemical composition of Egyptian TB-EO along with the above-mentioned biological activities. Our results may be considered as novel findings in the course of a search for new and active anticancer, anti-HSV-2 and antihypertensive agents, and expand the medicinal value of this plant and its phytochemicals in clinical practice.

Poly Organotin Acetates against DNA with Possible Implementation on Human Breast Cancer.

Two known tin-based polymers of formula {[R3Sn(CH3COO)]n} where R = n-Bu– (1) and R = Ph– (2),were evaluated for their in vitro biological properties. The compounds were characterized via their physical properties and FT-IR, 119Sn Mössbauer, and 1H NMR spectroscopic data. The molecular structures were confirmed by single-crystal X-Ray diffraction crystallography. The geometry around the tin(IV) ion is trigonal bi-pyramidal. Variations in O–Sn–O···Sn′ torsion angles lead to zig-zag and helical supramolecular assemblies for 1 and 2, respectively. The in vitro cell viability against human breast adenocarcinoma cancer cell lines: MCF-7 positive to estrogens receptors (ERs) and MDA-MB-231 negative to ERs upon their incubation with 1 and 2 was investigated. Their toxicity has been studied against normal human fetal lung fibroblast cells (MRC-5). Compounds 1 and 2 exhibit 134 and 223-fold respectively stronger antiproliferative activity against MDA-MB-231 than cisplatin. The type of the cell death caused by 1 or 2 was also determined using flow cytometry assay. The binding affinity of 1 and 2 towards the CT-DNA was suspected from the differentiation of the viscosity which occurred in the solution containing increasing amounts of 1 and 2. Changes in fluorescent emission light of Ethidium bromide (EB) in the presence of DNA confirmed the intercalation mode of interactions into DNA of both complexes 1 and 2 which have been ascertained from viscosity measurements. The corresponding apparent binding constants (Kapp) of 1 and 2 towards CT-DNA calculated through fluorescence spectra are 4.9 × 104 (1) and 7.3 × 104 (2) M−1 respectively. Finally, the type of DNA binding interactions with 1 and 2 was confirmed by docking studies.

Synthesis and Biological Evaluation of Indole-2-carbohydrazide Derivatives as Anticancer Agents with Anti-angiogenic and Antiproliferative Activities.

A novel series of indole-2-carbohydrazide derivatives were synthesized, characterized, and evaluated for their antiproliferative activities against two cancer cell lines, HCT116 and SW480, and a normal human fetal lung fibroblast cell line, MRC-5. Among this series, compound 24 f displayed potent cytotoxic activities in vitro against HCT116 and SW480 cell lines with GI50 values of 8.1 and 7.9 μm, respectively, and was inactive against MRC-5 cells. The newly synthesized compounds were also evaluated for anti-angiogenesis capabilities by chick chorioallantoic membrane, human umbilical vein endothelial cell (HUVEC) migration, and endothelial microtubule formation assays. Moreover, the effects of 24 f on the vascular endothelial growth factor receptor-2 and the signaling pathway in HUVECs indicated that this compound inhibits VEGFR-2 and its downstream related proteins. These results indicate that compound 24 f, as well as the other derivatives, are promising inhibitors of angiogenesis.

Protective effects of radish (Raphanus sativus L.) leaves extract against hydrogen peroxide-induced oxidative damage in human fetal lung fibroblast (MRC-5) cells

Natural antioxidants play a critical role in the promotion of good health for its prevention of oxidative stress. The main purpose of this study is to investigate the protective effects of radish leaves extract on the oxidative damage in human fetal lung fibroblast (MRC-5) cells. F2, a fraction of radish leaves extracts, which was fractionated by different polarity solvents and AB-8 macroporous resins column shows the best free radical scavenging ability, the highest total polyphenol contents (TPC), and the most potent protective effects on H2O2-induced oxidative damage in MRC-5 cells. The results indicated that pretreatment with F2 before the exposure of cells to H2O2 led to a significant increase in cell viability and internal antioxidant enzyme activities, and a decrease in the content of malondialdehyde (MDA). Furthermore, F2 attenuated the increase in intracellular reactive oxygen species (ROS) level and restored the loss of mitochondria membrane potential (MMP) caused by H2O2. In addition, pretreatment of F2 down-regulated the pro-apoptosis protein (Bax) and up-regulated the anti-apoptosis protein (Bcl-2) suggested its preliminary mechanism of protective effect. In summary, F2 from radish leaves might be used as a source of antioxidant for protecting the oxidative damage of lung.

Design and optimization of biocompatible polycaprolactone/poly (l-lactic-co-glycolic acid) scaffolds with and without microgrooves for tissue engineering applications.

This study investigated the effects of smooth and microgrooved membrane blends, with different polycaprolactone (PCL)/ poly(lactic-co-glycolic acid) (PLGA) ratios on the viability, proliferation, and adhesion of different mammalian cell types. The polymer matrices with and without microgrooves, obtained by solvent casting, were characterized by field-emission scanning electron microscopy, atomic force microscopy, contact angle and Young's modulus. Blend characterization showed an increase in roughness and stiffness of membranes with 30% PLGA, without any effect on the contact angle value. Pure PCL significantly decreased the viability of Vero, HaCaT, RAW 264.7, and human fetal lung and gingival fibroblast cells, whereas addition of increasing concentrations of PLGA led to a reduced cytotoxicity. Increased proliferation rates were observed for all cell lines. Fibroblasts adhered efficiently to smooth membranes of the PCL70/PLGA30 blend and pure PLGA, compared to pure PCL and silicone. Microgrooved membranes promoted similar cell adhesion for all groups. Microstructured membranes (15 and 20-μm wide grooves) promoted suitable orientation of fibroblasts in both PCL70/PLGA30 and pure PLGA, as compared to pure PCL. Neuronal cells of the dorsal root ganglion exhibited an oriented adhesion to all the tested microgrooved membranes. Data suggest a satisfactory safety profile for the microgrooved PCL70/PLGA30 blend, pointing out this polymer combination as a promising biomaterial for peripheral nerve regeneration when cell orientation is required. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1522-1534, 2018.

Antitumor activity of pyrrolizines and their Cu(II) complexes: Design, synthesis and cytotoxic screening with potential apoptosis-inducing activity

Two novel series including Schiff bases of the pyrrolizine-5-carboxamides and their Cu(II) complexes were designed, synthesized and analysed using spectral and analytical techniques. The analytical results indicated the formation of the complexes in 1:1 or 1:2 (Metal:Ligand) ratio. The geometry around the Cu centers was confirmed to be tetrahedral or octahedral. The cytotoxic activity of the new compounds was evaluated using MCF-7 (human breast adenocarcinoma), A2780 (human ovary adenocarcinoma) and HT29 (human colon adenocarcinoma), in addition to MRC5 (normal human fetal lung fibroblast) cells using the MTT cytotoxicity assay. The Schiff base 12c and the Cu complex 13b were the most active in the two series with IC50 values in the range of 0.14–2.54 μM against the three cell lines. Also, the Cu complex 13e showed excellent activity against HT29 with IC50 = 0.05μM. 7-Cyano-N-(4-methoxyphenyl)-6-((3-phenylallylidene) amino)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (12c) showed high selectivity (6–13 folds) for cancerous cells over normal cells; and it induced marginal increases in the G1 and S phases of MCF-7 cells during cell cycle analysis, while compound 13b increased the MCF-7 Sub-G1 proapoptotic population, and blocked cells in the G2-M phase in a dose dependent manner. The annexin V apoptosis assay revealed the ability of compounds 12c and 13b to increase the early apoptotic MCF-7 cell populations two and three fold, respectively. Furthermore, these findings were supported by data showing that the two compounds (12c and 13b) elicit cytotoxic activity. Taken together, the data presented in this study warrants further in vitro and in vivo investigations.

Synthesis, characterization and cytotoxic properties of bismuth(III) chloride complexes with heterocyclic thioamides

Abstract Bismuth(III) complexes of the formulae [BiCl3(MBZT)2] ·H2O} (1), {[BiCl2(µ2-Cl)(MMI)2]2·(CH3)2CO} (2), {[BiCl3(µ2-S-PYT)(PYT)]2} (3) {([BiCl2(MBZIM)4]+)·2(Cl-)·(H3O+) ·2H2O} (4) and [BiCl3(tHPMT)3] (5) (where MBZT: 2-mercaptobenzothiazole, MMI: 2-mercapto-1-methylimidazole, PYT: 2-mercaptopyridine, MBZIM: 2-mercaptobenzimidazole, tHPMT: 2-mercapto-3,4,5,6-tetrahydro-pyrimidine) are reported. The compounds were characterized by spectroscopic techniques including FT-IR, FT-Raman, UV-Vis, 1H-,13C-NMR spectroscopies, TG-DTA, e.a, molar conductivity and by single-crystal X-ray diffraction analysis. While 1, 4 and 5 are mononuclear compounds, 2 and 3 are dinuclear complexes in which the two Bi3+ ions are bridged through Cl- and SR groups respectively. Interestingly, 3 is the first example of dinuclear Bi3+ complex containing two Bi-(μ-SR)-Bi bridges between the two metal centers formed by covalent bonds. Compounds 1–5 were evaluated for their in vitro cytotoxic activity against human adenocarcinoma cervix (HeLa) and breast (MCF-7) cells. The toxicity of 1–5 was evaluated on normal human fetal lung fibroblast cells (MRC-5). The influence of 1–5, on the catalytic peroxidation of the linoleic acid by the enzyme lipoxygenase (LOX) was determined experimentally.

New metalo-therapeutics of NSAIDs against human breast cancer cells

The non steroidal anti-inflammatory drugs (NSAID's)-silver(I) metallodrugs of aspirin (aspH), salicylic acid (salH2), naproxen (napH) acid or p-hydrobenzoic acid (pHbzaH) and the mitochondriotropic triphenylarsine (tpAs) with the formulae [Ag(asp)(tpAs)3] (1), [Ag(salH)(tpAs)3] (2), [Ag(nap)(tpAs)3] (3) and {[Ag(pHbza)(tpAs)3]∙(dmf)} (4) and [Ag(tpAs)3(NO3)] (5) have been synthesized and characterized by m.p., FT-IR, UV-vis and 1H NMR, spectroscopic techniques and X-ray crystallography.The in vitro cytotoxic activity of 1–5 against human breast adenocarcinoma cancer cells: MCF-7 (positive to estrogen receptors (ERs)) and MDA-MB-231 (negative to estrogen receptors (ERs)) was evaluated. Compound 4 exhibits the stronger activity against MCF-7 (2.5 ± 0.1 μΜ), while 1 the strongest one against MDA-MB-231 (3.2 ± 0.3 μΜ). The IC50 values against normal human fetal lung fibroblast cells lie between 3.0 and 3.7 μΜ. The toxic effect of 1–5 was evaluated against normal human fetal lung fibroblast cells (MRC-5 cells). The IC50 values of 1–5 lie between 2.9 and 3.7 μΜ. The genotoxicity or not of 1–5 against MRC-5 cells was detected from the presence or absence of micronucleus using fluorescence microscopy. The presence of micronucleus in MRC-5 cells (3.0–3.7% in contrast to 1% of the untreated cells) confirms the in vitro toxic behaviour of the compounds. The apoptotic pathway, though the mitochondrion, was confirmed by cell cycle arrest (increasing of the apoptotic cells, in sub-G1 phase (3.5 (5) - 13.3% (4)) in contrast of 1.8% in the control group) and permeabilization of the mitochondrial membrane test (MMP assay). Moreover, the ability of 1–5 to interact with Calf Thymus (CT)-DNA was also studied. Compound 4 exhibits the highest DNA binding constant (Kb= (25.0 ± 9.7) × 104 M−1). The inhibitory activity of 1–5 against the enzyme lipoxygenase (LOX) is also investigated. The activity order is 1 > 4 > 3 > 2,5.

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.

Effects of Terminal Substitution and Iron Coordination on Antiproliferative Activity of l‐Proline‐salicylaldehyde–Thiosemicarbazone Hybrids

A series of five iron(III) complexes, namely [Fe(HL1)Cl2] (1), [Fe(HL2)Cl2]·1.6H2O (2·1.6H2O), [Fe(HL3)(MeOH)Cl2]·0.5H2O (3·0.5H2O), [Fe(HL4)(MeOH)Cl2]·0.5H2O (4·0.5H2O) and [Fe(HL4)(DMF)Cl2]·0.5Et2O·H2O (4′·0.5Et2O·H2O), where H2L1 = l‐proline‐salicylaldehyde–thiosemicarbazone (l‐Pro‐STSC), H2L2 = pyrrolidine‐substituted l‐Pro‐STSC, H2L3 = phenyl‐substituted l‐Pro‐STSC, and H2L4 = naphthyl‐substituted l‐Pro‐STSC, have been synthesized. The two ligand precursors (H2L3 and H2L4) and iron complexes were characterized by elemental analysis, spectroscopic methods (UV/Vis, IR, and NMR), ESI mass spectrometry, cyclic voltammetry, and single‐crystal X‐ray crystallography (1–3 and 4′). Magnetic properties of the five‐coordinate complex 2 and six‐coordinate complex 4 have also been investigated. The antiproliferative activity of the organic hybrids and their iron(III) complexes have been studied in vitro in five human cell lines and one murine cancer cell line, namely HeLa (cervical cancer), FemX (melanoma), A549 (alveolar basal adenocarcinoma), LS‐174 (colon cancer), MDA‐MB‐453 (breast cancer) and MS1 (transformed murine endothelial), as well as in human noncancerous fetal lung fibroblast cell line (MRC‐5). According to the structure–activity relationship, introduction of aromatic groups such as phenyl or naphthyl enhances the cytotoxic potency of the hybrids in the following order H2L1 < H2L2 < H2L3 < H2L4. Coordination of the hybrids to iron(III) improves their antiproliferative activity in the majority of investigated cell lines with exception of H2L3 in LS‐174, H2L4 in MS1, and both H2L3 and H2L4 in FemX cell lines, where an opposite effect was observed.

The leukotriene receptor antagonist pranlukast attenuates airway remodeling by suppressing TGF-β signaling

Background/ObjectiveAsthma is a chronic airway disease characterized by airway eosinophilic inflammation and remodeling, which are associated with a loss in lung function. Although both contribute significantly to asthma pathogenesis, mechanistic studies and drug discovery have focused on inflammatory targets. In this study, we investigated the effect of the leukotriene receptor antagonist pranlukast on allergic airway inflammation and remodeling in vivo and in vitro. MethodFour groups of female BALB/c mice (control; ovalbumin [OVA]-sensitized and -challenged; dimethyl sulfoxide [DMSO]-treated OVA; and pranlukast-treated OVA) were examined. Lung pathology, cytokine production, and airway hyperresponsiveness (AHR) measurements were compared among these groups. A human fetal lung fibroblast HFL-1 cell line was used in the peribranchial fibrosis analysis. ResultsOVA-sensitized and -challenged mice exhibited allergic airway inflammation and significant increases in Th2 cytokines. Pranlukast-treated mice showed significant attenuation of allergic airway inflammation. The pranlukast treatment decreased AHR and attenuated airway remodeling to goblet cell hyperplasia, collagen deposition, α-smooth muscle actin expression, and pro-fibrotic gene expression. We further demonstrated that pranlukast not only inhibited transforming growth factor-beta 1 (TGF-β1)-induced Smad signaling in human fetal lung fibroblast cells but also simultaneously reduced collagen synthesis and pro-fibrotic gene expression. ConclusionsThe leukotriene receptor antagonist pranlukast can reduce airway inflammation and remodeling by inhibiting TGF-β/Smad signaling in an OVA-sensitized and -challenged asthma mouse model, thus suppressing AHR.

Synthesis, crystal structure and antiproliferative mechanisms of 2-acetylpyridine-thiosemicarbazones Ga(III) with a greater selectivity against tumor cells

Thiosemicarbazone Ga(III) complexes (C3–C5) were synthesized and characterized by X-ray single crystal diffraction, and they were all 1:1 ligand/Ga(III) complexes. The antiproliferative activity of these Ga(III) complexes was tested against three cancer cell lines, demonstrating that Ga(III) complexes showed about 3–10 folds more anticancer activity than their ligands alone. Importantly, thiosemicarbazones and Ga(III) complexes have a low toxicity to human fetal lung fibroblast cells (MRC-5) and exhibit a high therapeutic index for tumor cells. The results of UV–visible spectroscopy showed that the binding constant of C4 with Topo-I-DNA was significantly higher than that of L4. The Ga(III) complex (C4) caused Topo-I inhibition and distinct DNA cleavage. Moreover, Ga(III) complex and thiosemicarbazone ligand prolonged the G1 phase in NCI-H460 cell cycle, which might be depended on the ability of these compounds to affect the expression of cell cycle related proteins.

Synthesis, characterization and biological activities of copper(II) complex of 2-Benzimidazolyl-urea and the nitrate salt of 2-Benzimidazolyl-urea

The synthesis of the complex {[Cu(BZIMU)2](NO3)2} (1) (BZIMU = 2-Benzimidazolyl-urea) is reported here. The complex 1 was characterized by elemental analysis, FT-IR, magnetic susceptibility and molar conductance measurements. The crystal structures of 1 and of the nitrate salt of [(BZIMUH+)(NO3)-] (2) were determined by X-ray diffraction analysis.The copper complex 1 and [(BZIMUH+)(NO3)-] (2) were evaluated for their in vitro cytotoxic activity (cell viability) against human cervix adenocarcinoma (HeLa) and human breast adenocarcinoma (MCF-7) cell line and normal human fetal lung fibroblast cells (MRC-5) with SRB assay.