Bioactivity and molecular docking of lactones isolated from Centaurea pseudosinaica Czerep.

Two cytotoxic sesquiterpene lactones, 17-epichlorohyssopifolin A (1) and chlorjanerin (2), and a monoterpene lactone, loliolide (3) were isolated from Centaurea pseudosinaica. The cytotoxicity of the total extract and terpenoids 1-3 were evaluated against three human cancer cells (HepG2, PC-3, and HT-29), along with the human normal primary epidermal keratinocytes (HEKa) cells. With IC50 values ranging between 0.6 ± 0.04 and 5.0 ± 0.61 µg/mL against HepG2; 0.2 ± 0.01 and 11.9 ± 1.31 µg/mL against PC-3, and 0.04 ± 0.013 and 8.9 ± 0.97 µg/mL against HT-29, the total extract, and lactones 1-3 demonstrated cytotoxic effects. Compound 1 displayed the strongest impact on all cancer cells and a slightly safe effect on the normal cells HEKa. Compound 1 caused accumulation of HepG2 and HT-29 cells in G1 phase as displayed cell cycle analysis. On the other hand, the cell distributions were increased in the S phase in PC-3 cells. Furthermore, 1 caused apoptosis in PC-3 and HePG2 cells with 91.50%, and 79.72 %, respectively. A higher fraction of necrotic cells was observed in HT-29 cells amounting to 23.60%. These results suggested that the promising cytotoxicity exhibited by 1 is brought by the apoptosis induction in the cancer cells, which were evaluated. As the compounds showed antiproliferative effect against the HT-29 cells, the docking simulation was performed aiming at determining how they would interact with the EGFR enzyme, whose PDB: 4I23 is considered one of the two distinct wild types of EGFR enzymes. The antibacterial activity results revealed that 3 showed the most remarkable antibacterial effects, especially against the examined Gram-positive bacteria. The total extract exhibited potent activity against all examined bacteria. The total extract showed a potent antifungal effect against two Candida and two Aspergillus pathogens. The antioxidant activity revealed the potency of the total extract and 3 as antioxidant candidates. The obtained results refer to the importance of Centaurea pseudosinaica as a source of potent antiproliferative agents and the whole plant as an antipathogenic and antioxidant agent.

Monoterpene Indole Alkaloids from the Aerial Parts of Rhazya stricta Induce Cytotoxicity and Apoptosis in Human Adenocarcinoma Cells.

Chromatographic investigation of the aerial parts of the Rhazya stricta (Apocynaceae) resulted in the isolation of two new monoterpene indole alkaloids, 6-nor-antirhine-N1-methyl (1) and razyamide (2), along with six known compounds, eburenine (3), epi-rhazyaminine (4), rhazizine (5), 20-epi-sitsirikine (6), antirhine (7), and 16-epi-stemmadenine-N-oxide (8). The chemical structures were established by various spectroscopic experiments. Compounds 1-8 exhibited cytotoxic effects against three cancer cells with IC50 values ranging between 5.1 ± 0.10 and 93.2 ± 9.73 µM against MCF-7; 5.1 ± 0.28 and 290.2 ± 7.50 µM against HepG2, and 3.1 ± 0.17 and 55.7 ± 4.29 µM against HeLa cells. Compound 2 showed the most potent cytotoxic effect against all cancer cell lines (MCF-7, HepG2 and HeLa with IC50 values = 5.1 ± 0.10, 5.1 ± 0.28, and 3.1 ± 0.17 µM, respectively). Furthermore, compound 2 revealed a significant increase in the apoptotic cell population of MCF-7, HepG2, and HeLa cells, with 31.4 ± 0.2%, 29.2 ± 0.5%, and 34.9 ± 0.6%, respectively. Compound 2 decreased the percentage of the phagocytic pathway on HepG2 cells by 15.0 ± 0.1%. These findings can explain the antiproliferative effect of compound 2.

Chemical Diversity and Bioactivities of Monoterpene Indole Alkaloids (MIAs) from Six Apocynaceae Genera.

By the end of the twentieth century, the interest in natural compounds as probable sources of drugs has declined and was replaced by other strategies such as molecular target-based drug discovery. However, in the recent times, natural compounds regained their position as extremely important source drug leads. Indole-containing compounds are under clinical use which includes vinblastine and vincristine (anticancer), atevirdine (anti-HIV), yohimbine (erectile dysfunction), reserpine (antihypertension), ajmalicine (vascular disorders), ajmaline (anti-arrhythmic), vincamine (vasodilator), etc. Monoterpene Indole Alkaloids (MIAs) deserve the curiosity and attention of researchers due to their chemical diversity and biological activities. These compounds were considered as an impending source of drug-lead. In this review 444 compounds, were identified from six genera belonging to the family Apocynaceae, will be discussed. These genera (Alstonia, Rauvolfia, Kopsia, Ervatamia, and Tabernaemontana, and Rhazya) consist of 400 members and represent 20% of Apocynaceae species. Only 30 (7.5%) species were investigated, whereas the rest are promising to be investigated. Eleven bioactivities, including antibacterial, antifungal, anti-inflammatory and immunosuppressant activities, were reported. Whereas cytotoxic effect represents 47% of the reported activities. Convincingly, the genera selected in this review are a wealthy source for future anticancer drug lead.

Synthesis, biological screening, and molecular docking of quinazolinone and quinazolinethione as phosphodiesterase 7 inhibitors.

N-Substituted isatoic anhydrides were used as starting materials for the synthesis of compounds 5-16 through alkali hydrolysis, Schiff base reactions, and oxidation. Compounds 18-23 were obtained by thionation of their oxo isosteres using Lawesson's reagent. Cyclocondesation of anthranilic acid with thiourea afforded compounds 25-27, which were S-alkylated to afford compounds 28-30, which were thionated using Lawesson's reagent to afford 31-33. The compounds were tested for their in vitro inhibitory activity against the phosphodiesterase 7A (PDE7A) enzyme compared with the selective PDE7 inhibitor BRL50481. All the compounds showed the inhibitory activity on the enzyme at micromolar levels. Compounds 9 and 25 showed the highest inhibitory activity on the enzyme: IC50 = 0.096 and 0.074 µM, respectively, comparable to BRL50481 (IC50 = 0.072 µM). The binding mode and binding affinity of the target compounds at the enzyme PDE7A-binding site were studied through molecular docking. Compounds 9 and 25 showed good recognition at the enzyme-binding site and were capable of binding in an inhibitory mode similar to the reference compound BRL50481, forming the necessary interactions with the key amino acids. Docking studies and enzyme assay were in agreement.

Two new polyacetylene derivatives from the Red Sea sponge Xestospongia sp.

Two new polyacetylenes (1 and 2), along with two known C-30 steroids (3 and 4) were identified from the Red Sea sponge, Xestospongia sp. The chemical structures were determined based on extensive spectroscopic measurements 1D (1H, 13C and DEPT) and 2D (COSY, HSQC and HMBC) NMR, UV, IR and MS. The new compounds 1 and 2 were evaluated for their antimicrobial and antitumor activities. 1 and 2 were active against multidrug- resistant bacteria with MICs ranged from 2.2 to 4.5 µM. No toxicity was recorded for the two tested compounds up to 5 µM using Artemia salina as a test organism. Compound 2 showed excellent antifungal activity against some pathogenic fungi such as Aspergillus niger and Candida albicans (MIC 2.2-2.5 µM) and antitumor activity against both Ehrlich ascites carcinoma and lymphocytic leukemia (LD50 5.0 µM).

Interface Immobilization Chemistry of cRGD-based Peptides Regulates Integrin Mediated Cell Adhesion.

The interaction of specific surface receptors of the integrin family with different extracellular matrix-based ligands is of utmost importance for the cellular adhesion process. A ligand consists of an integrin-binding group, here cyclic RGDfX, a spacer molecule that lifts the integrin-binding group from the surface and a surface anchoring group. c(-RGDfX-) peptides are bound to gold nanoparticle structured surfaces via polyproline, polyethylene glycol or aminohexanoic acid containing spacers of different lengths. Although keeping the integrin-binding c(-RGDfX-) peptides constant for all compounds, changes of the ligand's spacer chemistry and length reveal significant differences in cell adhesion activation and focal adhesion formation. Polyproline-based peptides demonstrate improved cell adhesion kinetics and focal adhesion formation compared with common aminohexanoic acid or polyethylene glycol spacers. Binding activity can additionally be improved by applying ligands with two head groups, inducing a multimeric effect. This study gives insights into spacer-based differences in integrin-driven cell adhesion processes and remarkably highlights the polyproline-based spacers as suitable ligand-presenting templates for surface functionalization.

A molecular toolkit for the functionalization of titanium-based biomaterials that selectively control integrin-mediated cell adhesion.

We present a click chemistry-based molecular toolkit for the biofunctionalization of materials to selectively control integrin-mediated cell adhesion. To this end, α5ß1-selective RGD peptidomimetics were covalently immobilized on Ti-based materials, and the capacity to promote the selective binding of α5ß1 was evaluated using a solid-phase integrin binding assay. This functionalization strategy yielded surfaces with a nine-fold increased affinity for α5ß1, in comparison to control samples, and total selectivity against the binding of the closely related integrin αvß3. Moreover, our methodology allowed the screening of several phosphonic acid containing anchoring units to find the best spacer-anchor moiety required for establishing an efficient binding to titanium and to promote selective integrin binding. The integrin subtype specificity of these biofunctionalized surfaces was further examined in vitro by inducing selective adhesion of genetically modified fibroblasts, which express exclusively the α5ß1 integrin. The versatility of our molecular toolkit was proven by shifting the cellular specificity of the materials from α5ß1- to αvß3-expressing fibroblasts by using an αvß3-selective peptidomimetic as coating molecule. The results shown here represent the first functionalization of Ti-based materials with α5ß1- or αvß3-selective peptidomimetics that allow an unprecedented control to discriminate between α5ß1- and αvß3-mediated adhesions. The role of these two integrins in different biological events is still a matter of debate and is frequently discussed in literature. Thus, such bioactive titanium surfaces will be of great relevance for the study of integrin-mediated cell adhesion and the development of new biomaterials targeting specific cell types.

An efficient approach to the synthesis of highly congested 9,10-dihydrophenanthrene-2,4-dicarbonitriles and their biological evaluation as antimicrobial agents.

An efficient and novel method for the synthesis in moderate to good yield (72%-84%) of a series of 3-amino-1-substituted-9,10-dihydrophenanthrene-2,4-dicarbonitriles 1-5 via one-pot multi-component reactions of aldehydes, malononitrile, 1-tetralone and ammonium acetate has been delineated. Cyclocondensation attempts of aminocyanophenanthrene derivatives 1, 2, 4 and 5 with acetic anhydride in the presence of conc. H2SO4 failed and instead the diacetylamino derivatives 10-13 were obtained. All prepared compounds were structurally elucidated by various spectroscopic methods and X-ray crystallography. N,N-diacetylamino-derivatives of phenanthrene have shown good antimicrobial activity.

2-[(2-Hy-droxy-naphthalen-1-yl)methyl-idene-amino]-5,6,7,8-tetra-hydro-4H-cyclo-hepta-[b]thio-phene-3-carbonitrile.

Two independent mol-ecules, A and B, comprise the asymmetric unit of the title compound, C(21)H(18)N(2)OS, with the difference in the angle of orientation between the naphthalene ring system and the mean plane of the cyclo-heptyl ring [16.13 (1) in A and 11.48 (5)° in B], being evident. The cyclo-heptyl ring adopts a distorted chair conformation in each mol-ecule with r.m.s. deviations of 0.2345 (4) (A) and 0.2302 (4) Š(B). Intra-molecular O-H⋯N hydrogen bonding generates planar six-membered S(6) loops with r.m.s. deviations of 0.0099 (1) (A) and 0.0286 (1) Š(B).

1,3-Diethyl-2-sulfanyl-idene-5-(2,4,5-trimeth-oxy-benzyl-idene)-1,3-diazinane-4,6-dione.

The title compound, C18H22N2O5S, is largely planar, with an r.m.s. deviation of 0.0546 (1) Šof atoms from the mean plane through all non-H atoms except for the methyl groups. The benzene and pyrimidine-dione rings are inclined to one another at a dihedral angle of 1.41 (7)°. In the crystal, weak C-H⋯O inter-actions connect the mol-ecules into chains propagating along the b-axis direction.

Toward the understanding of the metabolism of levodopa I. DFT investigation of the equilibrium geometries, acid-base properties and levodopa-water complexes.

Levodopa (LD) is used to increase dopamine level for treating Parkinson's disease. The major metabolism of LD to produce dopamine is decarboxylation. In order to understand the metabolism of LD; the electronic structure of levodopa was investigated at the Density Functional DFT/B3LYP level of theory using the 6-311+G** basis set, in the gas phase and in solution. LD is not planar, with the amino acid side chain acting as a free rotator around several single bonds. The potential energy surface is broad and flat. Full geometry optimization enabled locating and identifying the global minimum on this Potential energy surface (PES). All possible protonation/deprotonation forms of LD were examined and analyzed. Protonation/deprotonation is local in nature, i.e., is not transmitted through the molecular framework. The isogyric protonation/deprotonation reactions seem to involve two subsequent steps: First, deprotonation, then rearrangement to form H-bonded structures, which is the origin of the extra stability of the deprotonated forms. Natural bond orbital (NBO) analysis of LD and its deprotonated forms reveals detailed information of bonding characteristics and interactions across the molecular framework. The effect of deprotonation on the donor-acceptor interaction across the molecular framework and within the two subsystems has also been examined. Attempts to mimic the complex formation of LD with water have been performed.

(4Z)-4-Benzyl-idene-2-phenyl-1,3-oxazol-5(4H)-one.

In the title compound, C(17)H(13)NO(2), the benzene ring is twisted slightly out of the plane of the oxazole ring to which it is attached [dihedral angle = 7.98 (8)°]. Similarly, there is a twist [dihedral angle = 5.50 (8)°] between the oxazole and phenyl rings that are linked via the C=C bond [1.348 (2) Å]; the conformation about the latter is Z. In the crystal, the presence of C-H⋯O, C-H⋯π and π-π inter-actions [centroid-centroid distance = 3.5259 (9) Å] link the mol-ecules into a three-dimensional architecture.

N-(4-Sulfamoylphen-yl)acetamide.

In the title compound, C(8)H(10)N(2)O(3)S, the dihedral angle between the acetamide group and the benzene ring is 15.59 (12)° and the amino group is close to being perpendicular to the benzene ring [N-S-C(ar)-C(ar) (ar = aromatic) torsion angle = 109.4 (2)°]. In the crystal, mol-ecules are linked into supra-molecular tubes parallel to [001] by amine-amide N-H⋯O inter-actions and these are connected into the three-dimensional architecture by amide-sulfonamide N-H⋯O hydrogen bonds. The crystal studied was a racemic twin.

1-Phenyl-1H-pyrazole-4-carbaldehyde.

In the title mol-ecule, C(10)H(8)N(2)O, the five- and six-membered rings form a dihedral angle of 10.14 (9)°. The aldehyde group is almost coplanar with the pyrazole ring to which it is connected [O-C-C-C torsion angle = -179.35 (17)°]. In the crystal, inversion dimers are linked by four C-H⋯O inter-actions as the carbonyl O atom accepts two such bonds. The dimeric aggregates are linked into supra-molecular layers in the ac plane by C-H⋯π and π-π [ring centroid(pyrrole)⋯ring centroid(phen-yl) = 3.8058 (10) Å] inter-actions.

Modification of Sulfonated Polyethersulfone Membrane as a Selective Adsorbent for Co(II) Ions.

In the current study, a variety of sulfonated polyethersulfone (SPES)-based ion-exchange membranes were prepared and utilized as efficient and selective solid adsorbents for the detection of Co(II) ions in aquatic solutions. SPES membranes were treated with a variety of cations at a 2:1 ratio overnight. The produced materials were assessed via XRD, FT-IR, SEM, and TGA analyses. The structure of these materials was confirmed by FT-IR and XRD, which also confirmed the inclusion of Na+, NH4+, and amberlite on the SPES surface successfully. TGA analysis showed that the thermal stabilities of these materials were enhanced, and the order of stability was NH4-SPES > SPES > Na-SPES > A-SPES. Furthermore, the efficiency of these modified membranes for the determination and adsorption of a variety of metal ions was also examined by the ICP-OES analytical technique. A-SPES expressed a powerful efficiency of adsorption, and it showed an efficient as well as quantitative adsorption at pH = 6. Moreover, A-SPES displayed the highest adsorption capacity of 90.13 mg/g for Co(II) through the Langmuir adsorption isotherm.

Rapid and sensitive electrochemical sensor of cross-linked polyaniline/oxidized carbon nanomaterials core-shell nanocomposites for determination of 2,4-dichlorophenol.

Nanocomposites (NCs) of crosslinked polyaniline (CPA)-coated oxidized carbon nanomaterials (OXCNMs) were fabricated as a very sensitive and simple electrochemical sensor to be utilized in 2,4-dichlorophenol (2,4-DCPH) detection. CPA/OXCNMs NCs were prepared by chemical copolymerization of polyaniline with triphenylamine and p-phenylenediamine in the presence of OXCNMs. The CPA/GO-OXSWCNTNCs exhibited a higher affinity for the oxidation of chlorophenols compared to the glassy carbon electrode (GCE), CPA/GCE, and other NCs. Cyclic voltammetry was performed to investigate and assess the electrocatalytic oxidation of 2,4-DCPH on the modified GCE. The compound yielded a well-defined voltammetric response in a Britton-Robinson buffer (pH 5) at 0.54 V (vs. silver chloride electrode). Quantitative determination of 2,4-DCPH was performed by differential pulse voltammetry under optimal conditions in the concentration range of 0.05 to 1.2 nmol L-1, and a linear calibration graph was obtained. The detection limit (S/N = 3) was found to be 4.2 nmol L-1. In addition, the results demonstrated that the CPA/GO-OXSWCNTs/GCE sensor exhibited a strong anti-interference ability, reproducibility, and stability. The prepared CPA/GO-OXSWCNTs/GCE sensor was used to rapidly detect 2,4-DCPH with a high degree of sensitivity in fish farm water with proven levels of satisfactory recoveries.

Synthesis and characterization of metal nanoparticles templated chitosan-SiO2 catalyst for the reduction of nitrophenols and dyes.

Different metal nanoparticles (MNPs) templated on chitosan-silica (CH-SiO2) nanocomposite fiber were prepared via simple and fast method of the metal ions uptake by fiber and their subseqent reduction using strong reducing agent. The performance difference of CH-SiO2 templated with Cu, Co, Ag and Ni nanoparticles for both reduction of 4-nitroaniline (4-NA) and decolorization of congo red (CR) was investigated. The Cu nanoparticles loaded CH-SiO2 (Cu/CH-SiO2), showed high catalytic efficiencies in the reduction of 4-NA and CR, as compared to other loaded MNP fibers. The apparent rate constants of 6.17 × 10-3 s-1 and 1.68 × 10-2 s-1 and turnover frequencies (TOF) of 4.693 h-1 and 3.965 h-1 were observed for the reduction of 4-NA and CR, respectively. In addition, the catalytic activity of Cu/CH-SiO2 catalyst was also examined and found efficient in the reduction of nitrophenols (2-NP, 3-NP and 4-NP), and other dyes. Thus, Cu/CH-SiO2 with excellent catalytic activity can also be employed for other applications.

Chitosan coated cotton cloth supported zero-valent nanoparticles: Simple but economically viable, efficient and easily retrievable catalysts.

A simple, economically viable and fast method has been utilized for the preparation of highly active metal nanoparticles (MNPs) in coating layer of chitosan (CH) over cellulose microfibers of cotton cloth (CC). 2 wt% of CH solution was used for the coating of CC strips (CC-CH), and were kept in aqueous solutions of metal salts to adsorb metal ions. The CC-CH templated with metal ions were then treated with aqueous solution of NaBH4 to reduce the metal ions into zero-valent metal nanoparticles (M0). The CC-CH strips loaded with M0 were characterized by XRD, XPS, ATR-FTIR, FE-SEM and TGA, which indicates the successful synthesis of MNPs by this method. The M0/CC-CH strips were used as an efficient catalyst for the model reduction reaction of nitrophenol and toxic organic dyes. Among all the prepaped samples, Fe/CC-CH showed good catalytic activity for 4-NP and Rh-B dye reduction in the presence of NaBH4 with rate constants of 0.2937 min-1 and 0.3804 min-1, respectively. Moreover Fe/CC-CH has good catalytic reduction ability for MO and MB having rate constants equal to 0.1698 and 0.2802 min-1, respectively. Beside the good catalytic ability, it could be easily recoverable as compared to other available techniques. The recovery was completed by simply pulling the strip from the reaction matrix after completion of the reaction and can be used several times.

Cytotoxic Metabolites from Callyspongia siphonella Display Antiproliferative Activity by Inducing Apoptosis in HCT-116 Cells.

OBJECTIVES: To evaluate the antiproliferative effect of the isolated metabolites from Callyspongia siphonella. METHODS: Different chromatographic methods have been done on the organic extract of the marine sponge aiming at isolating the bioactive metabolites. The cytotoxicity of the isolated compounds has been evaluated against the human colorectal cancer cell line; HCT-116, employing SRB assay. The flow cytometry assay was applied to measure the cell cycle analysis. RESULTS: Six metabolites (1-6) were obtained. The compounds 4-6 exhibited IC50 values (µM ± SD) of 95.80± 1.34, 14.8 ± 2.33, and 19.8 ± 3.78, respectively. Cell cycle distribution analysis revealed that sipholenol A (5) and sipholenol L (6) induced G2/M and S phase arrest with concomitant increase in the pre-G cell population. Furthermore, 5 and 6 increased the nuclear expression of the pro-apoptotic protein-cleaved caspase-3 that effectively drives cellular apoptosis via caspase-3-dependent pathway. CONCLUSIONS: The antiproliferative activity of 5 and 6 can be recognized, at least partly, due to their ability to induce cellular apoptosis. SUMMARY: Several metabolites were isolated from the marine sponge Callyspongia siphonella. Sipholenol A and sipholenol L exhibited effective cytotoxicity against HCT-116 cells. The observed cytotoxicity involves induction of cellular apoptosis. Abbreviation used: A549 (human lung carcinoma), Caco-2 (Human ColonCarcinoma), CHCl3 (Chloroform), HCT 116 (Human Colon Carcinoma), HepG2 (Liver Hepatocellular Carcinoma), HT-29 (Human Colorectal Adenocarcinoma), MCF-7 (Michigan Cancer Foundation-7; Human Breast Adenocarcinoma), MeOH (Methanol), NMR Nuclear Magnetic Resonance), PBS (Phosphate Buffered Saline), PC-3 (Human Prostate Cancer), PTLC (Preparative Thin Layer Chromatography), RPMI-1640 (Roswell Park Memorial Institute medium), TLC (ThinLayer Chromatography).

Erratum: (4Z)-4-Benzyl-idene-2-phenyl-1,3-oxazol-5(4H)-one. Corrigendum.

In the paper by Asiri et al. [Acta Cryst. (2012), E68, o1154], the title and the chemical name of one of the reagents used in the synthesis are corrected.[This corrects the article DOI: 10.1107/S1600536812011579.].