A ruthenium(II)-trithiacyclononane curcuminate complex: Synthesis,characterization, DNA-interaction,and cytotoxic activity

The coordination of ruthenium(II) complexes to anionic oxygen-based donors are very rare. This study describes a simple, one-pot method for obtaining [ruthenium(II)(trithiacyclononane)(curcumin)(S-DMSO)]Cl (1) in 37% yield. The structural characterization of complex 1 by elemental analysis, FT-IR, 1-D and 2-D NMR, ESI⁺-MS as well as UV–vis and fluorescence spectroscopies are presented. The DNA-melting temperature (T_m) assay shows that salmon sperm DNA (smDNA) in the presence of complex 1 has a higher melting temperature, with ΔT_m = 7.4 °C, while in the presence of curcumin the melting temperature remains unaltered. The in vitro cytotoxic activities of curcumin and complex 1 were investigated using the tumor human prostate cell line, PC-3, and the healthy cell line, PNT-2. Complex 1 is innocuous toward normal prostate epithelial cells and, whereas curcumin is toxic, with inhibition rates of ca. 35 and 65% at 50 and 80 μM, respectively. On the tumor cell line PC-3, complex 1 did not cause viability changes, whereas curcumin exhibited dose-dependent inhibition, with ca. 73% inhibition at the highest concentration tested, i.e. 80 μM. This study suggests that coordination with the trithiacyclononane ruthenium(II) scaffold stabilizes the photochemical properties of curcumin and strongly changes its biologic activity.     

New salen-type manganese(III) Schiff base complexes derived from meso-1,2-diphenyl-1,2-ethylenediamine: In vitro anticancer activity,mechanism of action,and molecular docking studies

Four new manganese(III) Schiff base complexes (1–4) were synthesized and characterized. The complexes have general formula [MnClL^x] in which L represents a Schiff base ligand derived from condensation of meso-1,2-diphenyl-1,2-ethylenediamine with salicylaldehyde or its 3-OMe-, 5-Br-, or 5-OMe-derivatives (x = 1–4, respectively). The crystal structure of [MnClL¹] (1) was characterized by X-ray crystallography. The in vitro anticancer activity of these complexes was evaluated by MTT and apoptosis assays against human breast (MCF-7) and liver (Hep G2) cancer cells. The complexes exhibited considerable antiproliferative activity against both cell lines (IC₅₀ = 10.8–21.02 μM) comparable to cis-platin, except 4 (MCF-7). The highest activity was found for 1 with IC₅₀ values of 13.62 μM (MCF-7) and 10.8 μM (Hep G2). Flow cytometry experiments showed that 1 induced apoptosis on MCF-7 tumor cell line. Docking simulations using AUTODOCK were also carried out. The results showed that all complexes fitted into the minor groove region of DNA.     

Anticancer activity of Ophiobolin A,isolated from the endophytic fungus Bipolaris setariae

The present work describes the anticancer activity of Ophiobolin A isolated from the endophytic fungus Bipolaris setariae. Ophiobolin A was isolated using preparative HPLC and its structure was confirmed by HRMS, ¹H NMR, ¹³C NMR, COSY, DEPT, HSQC and HMBC. It inhibited solid and haematological cancer cell proliferation with IC₅₀ of 0.4–4.3 μM. In comparison, IC₅₀ against normal cells was 20.9 μM. It was found to inhibit the phosphorylation of S6 (IC₅₀ = 1.9 ± 0.2 μM), ERK (IC₅₀ = 0.28 ± 0.02 μM) and RB (IC₅₀ = 1.42 ± 0.1 μM), the effector proteins of PI3K/mTOR, Ras/Raf/ERK and CDK/RB pathways, respectively. It induced apoptosis and inhibited cell cycle progression in MDA-MB-231 cancer cells with concomitant inhibition of signalling proteins. Thus, this study reveals that anticancer activity of Ophiobolin A is associated with simultaneous inhibition of multiple oncogenic signalling pathways namely PI3K/mTOR, Ras/Raf/ERK and CDK/RB.     

Liquid Chromatographic Analysis of Various Formulations Containing Emtricitabine

A gradient liquid chromatographic (LC) method for control of emtricitabine (FTC) was validated for the analysis of FTC formulations (capsules and oral solution) and fixed-dose-combination tablets containing FTC [FTC combined with tenofovir disoproxil fumarate (TDF) and FTC combined with TDF and efavirenz (EFV)]. The method is based on the purity test recently prescribed in the International Pharmacopoeia and uses a Hypersil BDS C18 column (25 cm × 4.6 mm i.d.), 5 μm kept at a temperature of 35 °C. Other reversed-phase columns were also investigated. The mobile phases for gradient elution consist of acetonitrile, phosphate buffer and water. The flow rate is 1.0 mL min⁻¹ and UV detection is performed at 280 nm. The method is capable of separating the main components from one another, from the inactive ingredients and from the main degradation products. The method was validated with respect to accuracy, precision, sensitivity and linearity for each component and the solution media were optimized. Finally, commercial FTC capsules, FTC oral solution, FTC/TDF tablets and FTC/TDF/EFV tablets were examined.

     

Chemical composition and in vitro antibacterial and antiproliferative activities of the essential oil from the leaves of Psidium myrtoides O. Berg (Myrtaceae)

In this study, the chemical composition and antibacterial and antiproliferative potential of the essential oil obtained from fresh leaves of Psidium myrtoides (PM-EO) against oral pathogens and human tumour cell lines were investigated for the first time. GC-FID and GC-MS analyses showed that trans-β-caryophyllene (30.9%), α-humulene (15.9%), α-copaene (7.8%), caryophyllene oxide (7.3%) and α-bisabolol (5.3%) are the major constituents of PM-EO. The antibacterial activity of PM-EO against a panel of oral pathogens was investigated in terms of their minimal inhibitory concentrations (MIC) using the broth microdilution method. PM-EO displayed moderate activity against Streptococcus mitis (MIC = 100 μg/mL), S. sanguinis (MIC = 100 μg/mL), S. sobrinus (MIC = 250 μg/mL), and S. salivarius (MIC = 250 μg/mL), and strong activity against S. mutans (MIC = 62.5 μg/mL). The antiproliferative activity in normal (GM07492A, lung fibroblasts) and tumour cell lines (MCF-7, HeLa, and M059 J) was performed using the XTT assay. PM-EO showed 50% inhibition of normal cell growth at 359.8 ± 6.3 μg/mL. Antiproliferative activity was observed against human tumour cell lines, with IC₅₀ values significantly lower than that obtained for the normal cell line, demonstrating IC₅₀ values for MCF-7 cells (254.5 ± 1.6 μg/mL), HeLa cells (324.2 ± 41.4 μg/mL) and M059 J cells (289.3 ± 10.9 μg/mL). Therefore, the cytotoxicity of PM-EO had little influence on the antibacterial effect, since it showed antibacterial activity at lower concentrations. Our results suggest that PM-EO is a promising source of new antibacterial and antitumour agents.     

Hepatoprotective and neuroprotective tocopherol analogues isolated from the peels of Citrus unshiu Marcovich

Three tocopherol analogues methoxytocopherol (1), α-tocopherol (2) and γ-tocopherol (3) were isolated from the peels of Citrus unshiu Marcovich. The protective effects of the isolated compounds against tert-butyl hydroperoxide-induced hepatotoxicity in human liver-derived HepG2 cells and glutamate-induced oxidative stress in HT22-immortalised hippocampal cells were evaluated. Compounds 1–3 were significantly protective in HepG2 cells with EC₅₀ values of 21.22 ± 2.01, 25.21 ± 2.11 and 25.25 ± 1.21 μM, respectively, and in HT22 cells, compounds 1–3 had EC₅₀ values of 20.62 ± 1.36, 6.44 ± 1.65 and 9.52 ± 1.54 μM, respectively.     

Neuroprotective effects of Cassia tora against paraquat-induced neurodegeneration: relevance for Parkinson’s disease

The aim of the present study was to determine whether Cassia tora extracts could reverse the oxidative stress-induced neurodegeneration in a Parkinson’s disease in vitro model. The leaves were treated with ethyl acetate (CtEA) or methanol (CtME). The extracts were first analysed by HPLC for their phenolic content and then tested for their neuroprotective effects in human SK-N-SH neuroblastoma cells. Cells were pre-treated with various concentrations of extracts followed by incubation with paraquat (14 μM). Firstly, pre-treatment of SK-N-SH cells with 100 μg/mL of CtEA or CtME significantly reduced the paraquat-induced production of reactive oxygen species. Furthermore, both CtEA and CtME reduced the paraquat-induced apoptosis. Moreover, there was a significant reduction of paraquat-induced DNA damage in SK-N-SH cells pre-treated with CtEA or CtME. Finally, both extracts significantly inhibited paraquat-dependent lipid peroxidation. Altogether, these in vitro data establish C. tora as a possible anti-Parkinson natural remedy.     

Liquid Chromatographic Analysis of Various Formulations Containing Emtricitabine

A gradient liquid chromatographic (LC) method for control of emtricitabine (FTC) was validated for the analysis of FTC formulations (capsules and oral solution) and fixed-dose-combination tablets containing FTC [FTC combined with tenofovir disoproxil fumarate (TDF) and FTC combined with TDF and efavirenz (EFV)]. The method is based on the purity test recently prescribed in the International Pharmacopoeia and uses a Hypersil BDS C18 column (25 cm × 4.6 mm i.d.), 5 μm kept at a temperature of 35 °C. Other reversed-phase columns were also investigated. The mobile phases for gradient elution consist of acetonitrile, phosphate buffer and water. The flow rate is 1.0 mL min^?1 and UV detection is performed at 280 nm. The method is capable of separating the main components from one another, from the inactive ingredients and from the main degradation products. The method was validated with respect to accuracy, precision, sensitivity and linearity for each component and the solution media were optimized. Finally, commercial FTC capsules, FTC oral solution, FTC/TDF tablets and FTC/TDF/EFV tablets were examined.     

Aldose reductase inhibitory activity studies of THERACURMIN

THERACURMIN a commercially available nano-dispersion of curcumin used to treat after effects of alcohol has been evaluated for in vitro ARI activity on Aldose reductase isolated from the bovine lens. As envisaged, the product displays better ARI activity with IC₅₀ value of 3 μM. The observed ARI activity of THERACURMIN is of therapeutic significance as the limited bioavailability of curcumin limits its clinical use.     

Antiproliferative effect of isolated isoquinoline alkaloid from Mucuna pruriens seeds in hepatic carcinoma cells

The present study was undertaken to investigate the antiproliferative action of isolated M1 (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) from Mucuna pruriens seeds using human hepatic carcinoma cell line (Huh-7 cells). Initially, docking studies was performed to find out the binding affinities of M1 to caspase-3 and 8 enzymes. Later, cytotoxic action of M1 was measured by cell growth inhibition (MTT), followed by caspase-3 and 8 enzymes assay colorimetrically. Our results collectively suggested that M1 had strong binding affinity to caspase-8 in molecular modelling. M1 possessed antiproliferative activity on Huh-7 cells (EC₅₀ = 13.97 μM) and also inhibited the action of caspase-8 enzyme, signified process of apoptosis. M1 was active against Huh-7 cells that may be useful for future hepatic cancer treatment.     

Curcumin Inhibits the Sortase A Activity of the Streptococcus mutans UA159

Streptococcus mutans (S. mutans) forms part of the commensal microflora and is deemed to be the major pathogen responsible for the generation of dental caries. The enzyme, sortase A enzyme, modulates the surface properties and cariogenicity of S. mutans. Curcumin has been reported to be an inhibitor of Staphylococcus aureus sortase A. In this study, inhibition of a purified S. mutans UA159 sortase A by curcumin was evaluated. Curcumin exerted strong inhibitory activity with a half maximal inhibitory concentration (IC₅₀) of 10.2?±?0.7 μM which was lower than the minimum inhibitory concentration of 175 μM and the minimum bactericidal concentration of 350 μM. These results indicated that curcumin is a S. mutans UA159 sortase A inhibitor and therefore represents as a promising anticaries agent.     

New 3D and 2D supramolecular heteroleptic palladium(II) dithiocarbamates as potent anticancer agents

Three new heteroleptic palladium(II) dithiocarbamates with better in vitro anticancer activity than cisplatin were synthesized and characterized by different analytical techniques, elemental analysis, FTIR, NMR, and single crystal X-ray diffraction analysis. The Pd center is chelated by dithiocarbamate ligand {4-benzylpiperazine-1-carbodithioate (1) and (3) or (4-(2-methoxyphenyl)piperazine-1-carbodithioate (2)}, triorganophosphine {tris-(4-flourophenyl)-phosphine (1) and (2) or tris-(4-chlorophenyl)phosphine (3)}, and a chloro-group, resulting in a square planar geometry. The packing diagram reveals a 3D network (1 and 2) and a 2D network (3) composed of various 1D chains in which the molecules are linked via hydrogen bonds (1–3) and halide?π (1, 3) interactions. The anticancer activities of complexes against HeLa cell line varies in the sequence 2 (23.438 μM) > 1 (38.293 μM) > 3 (47.554 μM) > cisplatin (78.075 μM). The cytotoxicity of these complexes is due to their strong induction of oxidative stress and DNA-damage ability leading to apoptosis.     

Pradimicin-IRD from Amycolatopsis sp. IRD-009 and its antimicrobial and cytotoxic activities

A new polycyclic antibiotic, pradimicin-IRD, was isolated from actinobacteria Amycolatopsis sp. IRD-009 recovered from soil of Brazilian rainforest undergoing restoration area. This molecule is the major compound produced in solid culture media. The new compound was detected by a focused method of precursor ion (high-performance liquid chromatography coupled to tandem mass spectrometer) developed previously to identify unusual aminoglycosyl sugar moieties. The compound was isolated and its structure was, therefore, elucidated by high-resolution mass spectrometry, and 1D and 2D nuclear magnetic resonance experiments. Pradimicin-IRD displayed potential antimicrobial activity against Streptococcus agalactiae (MIC 3.1 μg/mL), Pseudomonas aeruginosa (MIC 3.1 μg/mL) and Staphylococcus aureus (MIC 3.1 μg/mL), and also cytotoxicity against tumour and non-tumour cell lines with IC₅₀ values ranging from 0.8 μM in HCT-116 colon carcinoma cells to 2.7 μM in MM 200 melanoma cells. Particularly, these biological properties are described for the first time for this chemical class.     

Prisconnatanones A,a cytotoxic naphthoquinone from Prismatomeris connata,suppresses the proliferation of human laryngocarcinoma HEp-2 cells in vitro

Prisconnatanones A (Priscon-A) is a rare tetrahydroanthraquinone isolated from herbal Prismatomeris connate. In this study, we examine its anti-tumour activity on human laryngocarcinoma HEp-2 cells in vitro. The CCK-8 assay was performed to evaluate its cytotoxicity. Cell cycle and apoptosis were analysed using flow cytometric analysis. Here, we showed Priscon-A inhibited the proliferation of HEp-2 cells in a dose-dependent manner, and at 5 μM it almost completely inhibited cell growth. Its cytotoxicity was associated with the cell cycle arrest at G2/M phase. The Annexin V-FITC/PI binding assay showed that the cell death induced by Priscon-A was associated with apoptosis. And, western blot analysis revealed that the levels of the apoptosis protein, cleaved caspase-3, PARP, p21 and Bax protein increased, while the level of anti-apoptosis protein Bcl-2 decreased.. These data demonstrated that Priscon-A significantly inhibited HEp-2 cell growth, induced the cell cycle arrest at the G2/M phase and efficiently induced cell apoptosis.     

Trixis angustifolia hexanic extract displays synergistic antibacterial activity against M. tuberculosis

A phytochemical and antibacterial study of Trixis angustifolia, a species endemic to Mexico, was performed allowing the isolation of six flavones. The minimal inhibitory concentration (MIC) of the hexanic extract, against Mycobacterium tuberculosis H37Rv was 25 μg/mL. The hexanic extract caused a significant inhibition of intracellular mycobacterial growth at 12.5 μg/mL. The biodirected assay of hexane extract enabled the detection of an active fraction (AF) against M. tuberculosis (MIC = 12.5 μg/mL), and a major flavone 1 (pebrellin) with no antimycobacterial activity (MIC > 200 μg/mL). A subsequent combination antimicrobial assay showed a synergistic antimycobacterial effect of AF in combination with pebrellin; the results of the synergistic activity suggest that the antimycobacterial activity found in T. angustifolia is due to the combined action of diverse metabolites present in the plant.     

A new coumarin from Juglans mandshurica Maxim induce apoptosis in hepatocarcinoma cells

In this study, a new coumarin, juglansoside C (1) was isolated from the bark of Juglans mandshurica. Its chemical structure was identified by comprehensive spectroscopic analyses. The in vitro cytotoxicity assay showed that 1 exhibited moderate cytotoxicity against human hepatocellular carcinoma Hep3B cells with an IC₅₀ value of 70.9 μM. Furthermore, Annexin V-FITC/PI staining assay indicated that 1 markedly induced apoptosis in Hep3B cells.     

A new aromatic glycoside and its anti-proliferative activities from the leaves of Bergenia purpurascens

Chemical investigation of the ethanolic extracts of the dried leaves of Bergenia purpurascens led to the isolation and identification of a new aromatic glycoside, 1-O-β-D-glucopyranosyl-2-methoxy-3-hydroxyl-phenylethene (1), along with other 19 known compounds (2–20). The structure of compound 1 was determined by a detailed analysis using various analytical techniques, including 1D and 2D NMR. In vitro anti-proliferative activities of compound 1 on five human cancer cell lines were evaluated. The results showed that compound 1 possessed the most potent effects with the IC₅₀ values of 14.36 ± 1.04 μM against T24 cells. The further bioactivity analysis showed that compound 1 induced apoptosis of T24 cells, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activation of caspase-3 for causing cell apoptosis. The present investigation illustrated compound 1 might be used as a potential antitumour chemotherapy candidate.     

Effect of Agave americana L. on the human,and Aspergillus oryzae S2 α-amylase inhibitions

Among phenolic compounds, Agave americana L. extract contained puerarin (38.4%) and p-coumaric acid (12.29%) (pCa). From the Lineweaver–Burk plots, pCa and puerarin demonstrated a competitive and a non competitive inhibitions towards human α-amylase activity, respectively. PCa exhibited a higher human inhibitory activity with an IC₅₀ of 98.8 μM which was about 2.3 times than acarbose. Puerarin (IC₅₀ = 3.87 μM) and pCa (IC₅₀ = 10.16 μM) also showed an excellent inhibition for Aspergillus oryzae S2 α-amylase activity. The inhibitions of the described biocatalysts compounds towards both amylases were significantly decreased when they were pre-incubated with starch. The binding modes of these compounds were evaluated in silico. The binding efficiency order of these molecules in terms of polar contact numbers for both enzymes was in agreement with the in vitro studies. These findings provided a rational reason to establish the isolated compounds capability as therapeutic target for hyperglycaemia modulation and antifungal therapy.     

Synthesis,cytotoxicity, and interaction with DNA of platinum(II) complexes of (1R,2R)-N1-2-amyl-1,2-diaminocyclohexane

(1R,2R)-N¹-2-amyl-1,2-diaminocyclohexane, which has an amyl substituent as compared with 1,2-diaminocyclohexane, was used as the carrier group to construct three platinum(II) complexes. MTT assay revealed that the complexes showed decent cytotoxicity against all of the four tested tumor cell lines with the IC₅₀ values ranging from 1.08 to 253.36 μM. Particularly, the IC₅₀ values of 2 against A549 and HCT-116 reached 3.32 and 1.08 μM, respectively, which were much lower than those of cisplatin and oxaliplatin. Flow cytometry demonstrated that 2 inhibited HepG2 cells proliferation and caused cytotoxicity by inducing apoptosis and arresting cells in the G2 phase. Furthermore, agarose gel electrophoresis showed that 2 had the ability to interact with DNA in a manner different from cisplatin and oxaliplatin, indicating the carrier ligand with an alkyl moiety had an influence on the action mode of the complex.     

Synergistic Growth-Suppressive Effects of Quercetin and Cisplatin on HepG2 Human Hepatocellular Carcinoma Cells

Quercetin, a natural flavonoid, exhibits anticancer effects. The aim of this study is to determine whether the combination of quercetin with cisplatin, a conventional chemotherapeutic drug, would have synergistic suppressive effects on hepatocellular carcinoma (HCC) cells. To this end, HepG2 cells were exposed to quercetin (50 μM) or cisplatin (10 μM) alone or combination of both and cell proliferation and apoptosis were investigated. Our data revealed that the combination of quercetin and cisplatin was significantly (P?<?0.05) effective in inducing growth suppression and apoptosis in HepG2 cells, when compared with single agent treatment. Quercetin combined with cisplatin modulated the expression of numerous genes involved in cell cycle progression and apoptosis. Treatment with quercetin rather than cisplatin resulted in a marked elevation of p16 expression in HepG2 cells. Targeted reduction of p16 using RNA interference technology partially reversed quercetin-induced cell cycle G1 arrest and apoptosis in HepG2 cells. In conclusion, quercetin has suppressive activity against HCC cells through p16-mediated cell cycle arrest and apoptosis and its combination with cisplatin yielded synergistic inhibitory effects in suppressing cell growth and inducing apoptosis.