Antifungal and Cytotoxic Activity of Diterpenes and Bisnorsesquiterpenoides from the Latex of Euphorbia resinifera Berg.

Euphorbia resinifera latex has been extensively utilized in traditional medicine due to its range of bioactivities. Chromatographic separations on silica gel of ethanol extract of E. resinifera latex led to the development of a new procedure for isolating resiniferatoxin (4) via dried E. resinifera latex and the identification of nine compounds. Among these, catechol (7), protocatechuic acid (8) and 3,4-dihydroxyphenylacetic acid (9), known phenolic compounds, were identified for the first time in E. resinifera latex. Herein we investigated the effects of major compounds of the latex of E. resinifera on the yeast Saccharomyces cerevisiae, on the growth of Aspergillus carbonarius, a widespread fungal contaminant, and on the breast cancer cell line MCF7 as well as on MCF10A normal breast cells. 12-deoxyphorbol-13-isobutyrate-20-acetate (2) had an inhibiting effect on the growth of A. carbonarius, and 7-p-metoxyphenylacetate-3,8,12-triacetate ingol (3) showed a negative effect on yeast cell growth and also a cytotoxic effect on breast cancer cell line MCF7, but not on MCF10A cells. Deglucosyl euphorbioside A (5) and euphorbioside A (6) showed a discoloration effect that was possibly related to mitochondrial functionality in yeast, and also cytotoxicity only on the cancer cell line that was tested. Interestingly, treatment of MCF7 cells with 7-p-metoxyphenylacetate-3,8,12-triacetate ingol (3) and deglucosyl euphorbioside A (5) not only led to a specific cytotoxic effect but also to the increase in the level of intracellular ROS.

Chemical composition, antibacterial, antioxidant and insecticidal activities of moroccan Thapsia transtagana essential oil.

INTRODUCTION: The use of chemical products to neutralize microorganisms has always been a subject of discussion and research for alternative solutions, indeed, the use of essential oils has been a promising natural methodology. METHODS: In our study we used the essential oils from different parts of Thapsia transtagana (Apiaceae), obtained by hydrodistillation, were identified and using Gas chromatography-mass spectrometry (GC-MS) and Gas Chromatography-Flame Ionization Detection (GC/FID) methods and evaluated against several bacteria of Gram- and Gram + bacteria. Disk diffusion, Minimum Inhibitory Concentration (MIC) and Minimum Microbicidal Concentration (MMC) methods have been used. Free radical-scavenging activity and insecticidal activity of Thapsia transtagana essential oils were also identified. RESULTS: Majority products from different parts of Thapsia transtagana essential oil identified by GC-MS and GC/FID methods are 2,6-Dimethylnaphthalene, Pinane and Hexahydrofarnesyl acetone. The highest activity was found against Staphylococcus aureus using inflorescence essential oil with minimal inhibitory concentration value for 0,56 µg/µL. Insecticidal activity was also the subject of this study, roots and inflorescence essential oils demonstrated to have a remarkable potent against Acanthoscelides obtectus and Sitophilus oryzae using contact assessment, inhalation assessment and ingestion assessment tests. Insecticidal activity assay results showed a significant enhancement of mortality in both test insect pest on increasing the dose and exposure period. In the other hand, the different essential oils of Thapsia transtagana were evaluated for their radical scavenging activities by means of the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay. The strongest scavenging activity was observed in inflorescences essential oil fraction scavenged radicals effectively at 100% using 500 mgL-1 concentration. CONCLUSION: Its essential oils were proved to have strong antimicrobial, insecticidal and antioxidant activities that allows it to be used by the pharmaceutical and cosmetic industries as natural preservative.

Design, synthesis, and evaluation of cytotoxic activities of arylnaphthalene lignans and aza-analogs.

A concise and versatile synthetic strategy for the total synthesis of arylnaphthalene lignans and aza-analogs was developed. The main objective was to develop synthetic tactics for the creation of the lactone and lactam unit that would give access to an array of synthetic, natural, and/or bioactive compounds through rather simple chemical manipulation. The flexibility and potentiality of these new processes were further illustrated by the total synthesis of retrojusticidin B (13b), justicidin C (14b), and methoxy-vitedoamine A (22a). In this study, a series of novel aryl-naphthalene lignans and aza-analogs were synthesized, and the cytotoxic activities of all compounds on cancer cell growth were evaluated. The target compounds were structurally characterized by 1 H NMR (nuclear magnetic resonance), 13 C NMR, infrared, high-resolution mass spectrometry, and X-ray crystallography. The IC50 values of these compounds on five tumor cell lines (A549, HS683, MCF-7, SK-MEL-28, and B16-F1) were obtained by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay. Five of the compounds exhibited excellent activity compared to 5-fluorouracil and etoposide against the five cell lines tested, with IC50 values ranging from 1 to 10 µM.

Valorization of Opuntia ficus-Indica Pads and Steel Industry FeCl3-Rich Rejection for Removing Surfactant and Phenol from Oil Refinery Wastewater Through Coagulation-Flocculation.

BACKGROUND: Refinement of crude vegetable oil generates a large amount of wastewater and is a source of water pollution due to the presence of surfactants and phenols. Phenols are toxic aromatic compounds that can be lethal to fauna and flora, entraining the deceleration or blocking of the self-purification of biological treatments. In addition, surfactants can limit biological processes by inhibiting microorganisms that degrade organic matter. OBJECTIVES: The aim of the present study was to evaluate the treatment of refinery rejects loaded with phenols and detergents by coagulation flocculation using cactus pads (genus Opuntia) as a bio-flocculant and 30% iron(III) chloride (FeCl3) for surfactant and phenol removal. In addition, operating costs were evaluated for these pollution mitigation methods. METHODS: The effectiveness of cactus pads as a bio-flocculant and 30% FeCl3 for surfactant and phenol removal were studied using a jar test. The study was conducted on vegetable oil refinery wastewater from a refinery company in Casablanca, Morocco. RESULTS: The pollution load in wastewater varied widely from day to day. We evaluated the effect of cactus juice and 30% FeCl3 on high and low pollution loads. Opuntia pads showed a favorable potential for the treatment of low pollution load wastewater, with 78% and 90% of surfactant and phenol removed, respectively. However, the removal of high pollution load was less effective (42% and 41% removal of surfactant and phenol, respectively). The turbidity of low and high pollution load was reduced by 98.85% and 86%, respectively. The results demonstrate that 30% FeCl3 can effectively treat both low and high pollution loads (90% and 89% phenol removal, respectively, and 90% and 70% surfactant removal, respectively (optimal concentration 1.48 g/l). The turbidity was reduced by over 96% for both high and low pollutants. CONCLUSIONS: The results of the present study indicate that cactus as a natural flocculant and reject rich in FeCl3 could be effectively used for the low-cost effective treatment of crude vegetable oil refinery rejects. COMPETING INTERESTS: The authors declare no competing financial interests.

Synthesis and Biological Evaluation of New Naphthoquinones Derivatives.

New substituted 1,4-naphthoquinones have been prepared in good overall yields through the naphthol route. The cytotoxicity of these compounds was tested in vitro on MCF-7 breast tumor cells. The most active compound 14 displayed an IC50 of 15µM. OBJECTIVE: To investigate the cytotoxicity of new naphthoquinones derivatives on MCF-7 cells. METHODS: Synthesis of new naphtoquinones derivatives and in vitro evaluation of their cytotoxicity on MCF-7 cells (rezasurin cell-based assay). RESULTS: Starting from Ethyl 4-hydroxy-6,7-dimethoxy-2-naphthoate, four naphthoquinones were prepared and exhibited substantial cytotoxicity against MCF-7 cells. CONCLUSION: Preliminary studies of the structure-activity relationship have shown the influence of the structural parameters and, in particular, the nature of the naphthoquinone side chain.

Efficient synthesis and first regioselective C-6 direct arylation of imidazo[2,1-c][1,2,4]triazine scaffold and their evaluation in H2O2-induced oxidative stress.

Oxidative stress and apoptosis are both associated with various acute and chronic disorders. Thus, the aim of the present study is to synthesize imidazo[2,1-c][1,2,4]triazines derivatives and to evaluate their effects in H2O2-induced oxidative stress in human neuroblastoma cell line (SH-SY5Y cells). The effects of the compounds on cell viability were measured by MTT assay and the changes in stress and apoptosis-related proteins were investigated by PathScan® Stress and Apoptosis Signaling Antibody Array kit and Western Blot technique. In particular, four compounds were found to protect SH-SY5Y cells from H2O2-induced toxicity by increasing Bcl-2/Bax ratio, regulating PI3-K/Akt cascade and inhibiting the ERK pathway.

Synthetic Modification of 9α- and 9ß-Hydroxyparthenolide by Heck or Acylation Reactions and Evaluation of Cytotoxic Activities.

Motivated by the widely reported anticancer activity of parthenolides and their derivatives, a series of new substituted parthenolides was efficiently synthesized. Structural modifications were performed at the C-9 and C-13 positions of 9α- and 9ß-hydroxyparthenolide, which were isolated from the aerial parts of Anvillea radiata. Twenty-one derivatives were synthesized and evaluated for their in vitro cytotoxic activity against HS-683, SK-MEL-28, A549, and MCF-7 human cancer cell lines using the MTT colorimetric assay. Among the derivatives, seven exhibited excellent activity compared to 5-fluorouracil and etoposide against the four cell lines tested, with IC50 values ranging from 1.1 to 9.4 µM.

Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors.

An efficient synthetic strategy able to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton was developed. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally to support the SAR, a docking study was performed. A potent GSK3/CDK5 dual inhibitor (37, IC50 CDK5/GSK3 35/7 nM) was obtained. Best antiproliferative effects were obtained on lung and prostate cell lines with IC50 = 20 nM.

Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.

An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines.

Synthesis and biological evaluation of 9α- and 9ß-hydroxyamino-parthenolides as novel anticancer agents.

A series of 9α-hydroxyamino-parthenolides 3-10, 9ß-hydroxyamino-parthenolides 11-13 and 9α-hydroxy-1ß,10α-epoxyamino-parthenolides 15-19 were efficiently synthesized starting from 9α-hydroxyparthenolide 1 and 9ß-hydroxyparthenolide 2, which were isolated from Anvillea radiata. Compounds 1-13 and 15-19 were evaluated for their in vitro anticancer activity by the MTT colorimetric assay against one murine and six human cancer cell lines. This work provides new details about the structural requisites for anticancer activity.

Design, synthesis, and biological activity of pyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors.

The design, synthesis, and screening of dual PI3K/mTOR inhibitors that gave nanomolar enzymatic and cellular activities on both targets with an acceptable kinase selectivity profile are described. A docking study was performed to understand the binding mode of the compounds and to explain the differences in biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines and compared to those on a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast cancer cells and trigger apoptosis. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds or as a chemical series for further optimization to progress into in vivo experiments.

Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): potent cyclin-dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts.

The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3ß in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC(50) < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents.

Chemical composition and antibacterial activity of essential oil of Pulicaria odora L.

The chemical composition of the volatile oil constituent from Pulicaria odora L. roots has been analyzed by GC/MS. Twenty-seven components were identified, being thymol (47.83%) and its derivative isobutyrate (30.05%) the main constituents in the oil. Furthermore, the oil was tested against seven bacteria at different concentrations. Results showed that the oil exhibited a significant antibacterial activity.