Synthesis and cytotoxicity evaluation of d- and l-sugar-containing mono- and bidesmosidic ursane-type saponins.

Ursolic acid and uvaol are naturally occurring triterpenoids that exhibit a broad spectrum of pharmacological activities, including cytotoxicity. However, a primary challenge in the development of ursane-type pentacyclic triterpenoids for pharmacological use is their poor aqueous solubility, which can impede their effectiveness as therapeutics agents. In this study, we present the facile synthesis of ursolic acid monodesmosides and uvaol bidesmosides, incorporating naturally occurring and water-soluble pentoses and deoxyhexose sugar moieties of opposite d- and l-configurations at the C3 or C3/C28 positions of the ursane core. The twenty synthetic saponins were evaluated in vitro for their cytotoxicity against lung carcinoma (A549) and colorectal adenocarcinoma (DLD-1) cell lines. Notably, all the bidesmosidic uvaol saponins were shown to be cytotoxic as compared to their non-cytotoxic parent triterpenoid. For each series of ursane-type saponins, the most active compounds were 3-O-α-l-arabinopyranosyl ursolic acid (3h) and 3,28-di-O-α-l-rhamnopyranosyl uvaol (4f), showing IC50 values in the low micromolar range against A549 and DLD-1 cancer lines.

Antiproliferative and Anti-Inflammatory Effects of the Polyphenols Phloretin and Balsacone C in a Coculture of T Cells and Psoriatic Keratinocytes.

Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack of effectiveness and toxic side effects are the main concerns with conventional treatments, and research involving new antipsoriatic molecules is essential. In this study, the anti-inflammatory and antiproliferative effects of two natural polyphenols, phloretin and balsacone C, were investigated using the coculture of T cells and psoriatic keratinocytes. Phloretin exerted antiproliferative activity by regulating the expression of antigen Ki67 and proliferating cell nuclear antigen (PCNA). These effects were comparable to those of methotrexate, a reference treatment for moderate to severe psoriasis. With balsacone C, the expression of Ki67 was also reduced. Additionally, phloretin decreased the levels of multiple pro-inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor alpha (TNF-α). The increased interleukin-2 (IL-2) levels with phloretin and methotrexate also represented anti-inflammatory activity. Balsacone C and methotrexate decreased the levels of IL-1α and IL-1ß, but methotrexate exerted a higher reduction. In summary, the anti-inflammatory effects of phloretin were more pronounced than those of methotrexate and balsacone C. In addition, the expression of lymphocyte common antigen (CD45) was more similar to that of the healthy condition after using phloretin or methotrexate. Finally, phloretin stood out from the other compounds and appears promising for psoriasis treatment.

Phenolic compounds from Limonium densiflorum: a multifaceted approach to antioxidant, anti-inflammatory, anticancer, and anti-influenza activities.

Exploration of the hydroethanolic extracts from the halophyte Limonium densiflorum, led to the isolation of seven phenolic compounds: gallic acid, epigallocatechin gallate (EGCG), quercitrin, a mixture of myricetin 3-O-α-rhamnopyranoside + myricetin 3-O-L-arabinofuranoside, dihydrokaempferol, pinoresinol, and trans-N-ferulolyl tyramine. These compounds were assessed for anticancer, anti-influenza A virus, antioxidant, and anti-inflammatory properties. The results indicated that these compounds do not exhibit toxicity towards healthy cells (WS-1 and MDCK). Furthermore, they displayed strong antioxidant properties. Among these compounds, gallic acid, the mixture of myricetin 3-O-α-rhamnopyranoside + myricetin 3-O-L-arabinofuranoside, dihydrokaempferol, and pinoresinol, showed significant cytotoxicity against colon cancer cells (IC50: 1-39 µg/mL). EGCG, gallic acid, dihydrokaempferol, pinoresinol, and trans-N-ferulolyl tyramine demonstrated potent anti-inflammatory activity by reducing nitric oxide (NO) production and also inhibited the replication of the influenza A virus. Biological activities varied based on compound structure, with phenolic acids and flavonoid aglycones showing stronger effects than glycosylated compounds and lignans.

Potential bio-functional properties of Citrus aurantium L. leaf: chemical composition, antiviral activity on herpes simplex virus type-1, antiproliferative effects on human lung and colon cancer cells and oxidative protection.

This study examined the antioxidant, anticancer and antiviral properties of the methanolic extracts from bigarade (Citrus aurantium L.) leaves at two development stages. Ferulic acid, naringin and naringenin were the principal phenolic components of young and old leaves. The highest total antioxidant capacity was obtained in young leaf extracts (YLE). These latter also exhibited the highest antiradical DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) activities, while the highest iron chelating and reducing power activities were observed in old leaf extracts (OLE). The potent anticancer activity was observed in YLE for human lung carcinoma (A-549) and in OLE for colon adenocarcinoma (DLD-1) cells. YLE showed the highest virucidal effects as compared to OLE and the positive control acyclovir against herpes simplex virus type-1 (HSV-1) propagation in Vero cells during the absorption and replication periods. The young and old leaves might be a source of natural antioxidants and protective agents against oxidative damage.

Phytochemical investigation, antioxidant, anti-inflammatory and cytotoxic activities of Tunisian medicinal Tamarix africana Poir.

The current study aimed to evaluate Tunisian Tamarix africana Poir biological activities. In this study, novel biological activities of the shoot extracts related to their phenolics investigated. Secondary metabolite contents, antioxidant, anti-inflammatory and cytotoxic activities of four extracts (hexane, dichloromethane, methanol and water) were investigated. Antioxidant activities were assessed via in vitro and ex vivo assays. Besides, anticancer activity was investigated against human lung carcinoma (A-549) and colon adenocarcinoma (DLD-1) cells. The anti-inflammatory ability was evaluated via inhibition of LPS-induced NO production in RAW 264.7 macrophage cell lines. Methanol and water extracts displayed the highest antioxidant (IC50 = 3.3 and 4.3 µg/mL respectively), which are correlated activities correlated with phenolic contents. Hexane extract exhibited an important anti-inflammatory effect inhibiting NO ability by 100% at 80 µg/mL. Besides, T. africana extracts were found to be active against A-549 lung carcinoma cells with IC50 values ranging from 20 to 34 µg/mL. These results suggested that T. africana is considered as a potential source of readily accessible natural molecules with a promising effect on human health and diseases.

Phytochemical analysis, antioxidant, anticancer and anti-inflammatory activities of Lycium europaeum fruits.

Lycium europaeum is used as a medicinal herb in many countries. In this study, cyclohexane, dichloromethane, ethyl acetate, methanol and water were used as solvents in the extraction of L. europaeum fruits. The contents of total phenolics, total flavonoids, total tannins and condensed tannins as well as the biological activities of these extracts were investigated using various in vitro and ex vivo assays. Results showed that all solvent extracts of L. europaeum had no anticancer activity against cancerous (A-549 and DLD-1) and non-cancerous (WS-1) human cells. Methanol and ethyl acetate were the most effective solvent for extraction of phenolic compounds and also exhibited the highest antioxidant and anti-inflammatory activities. The methanol extract of L. europaeum fruits was the richest in phenolic compounds with the predominance of ferulic acid, catechin and narengin. These results supported the use of L. europaeum fruit as natural source of bioactive compound for pharmaceutical applications.

Total Synthesis of a Chimeric Glycolipid Bearing the Partially Acetylated Backbone of Sponge-Derived Agminoside E.

We describe the total synthesis of a chimeric glycolipid bearing both the partially acetylated backbone of sponge-derived agminoside E and the (R)-3-hydroxydecanoic acid chain of bacterial rhamnolipids. The branched pentaglucolipid skeleton was achieved using a [3 + 2] disconnection approach. The ß-(1 → 2) and ß-(1 → 4)-glycosidic bonds were synthesized through a combination of NIS/Yb(OTf)3- and TMSOTf-mediated stereoselective glycosylations of thiotolyl, N-phenyltrifluoroacetimidate, and trichloroacetimidate donors. Late-stage pentaacetylation, Staudinger reduction of a (2-azidomethyl)benzoyl group, followed by continuous-flow microfluidic hydrogenolysis completed the total synthesis of the structurally simplified glycolipid, whose partial acetylation pattern on the glycan part was identical to agminoside E. Our study lays the foundation for the total synthesis of sponge-derived agminosides and the understanding of their biological functions in sponges.

Effect of the Chromone Core Substitution of Dirchromone on the Resultant Biological Activities.

Dirchromone is a bioactive vinyl sulfoxide-bearing chromone first isolated from the shrub Dirca palustris. Altogether, 32 of its derivatives were prepared to assess the effect of substitution of its chromone core upon activities against cancer cell lines, Gram-positive bacteria, and fungi (such as Candida albicans). All compounds were synthesized following a synthetic strategy involving Pummerer and soft-enolization Baker-Venkataraman rearrangements. Substituent position changes induced little variability on the activities tested. There was no correlation between cytotoxic and antibacterial effects, suggesting different underlying mechanisms of action. In particular, hydroxy group and cyanide substituents diminished cytotoxicity, with the latter featuring enhanced antibacterial activity. Higher homologues of 6-alkoxydirchromones also exhibited progressively emerging antifungal activity. Other modifications had moderate effects on cytotoxicity with some derivatives leading to increased potency. This behavior highlights the robustness of the natural dirchromone pharmacophore toward decoration, thus paving the way for more elaborate future drug design.

Phenolic Extract from Aralia nudicaulis L. Rhizomes Inhibits Cellular Oxidative Stresses.

UV-B and IR-A radiation are important inducers of biological changes in skin involving ROS generation. The overloading of antioxidant defense mechanisms by ROS production could lead to photoaging and photocarcinogenesis processes. Various traditional usages are reported for Aralia nudicaulis L. extracts, including treatment of dermatological disorders. Antioxidant and anti-inflammatory properties have already been reported for other Aralia species possibly due to the presence of phenolic compounds. However, the phenolic composition and the potential activity of A. nudicaulis rhizomes extract against oxidative stress and UV/IR damages have not been investigated. The main aims of this study were to prepare a fraction enriched in phenolic compounds (FEPC) from A. nudicaulis rhizomes, to identify its major phenolic compounds and to assess its potential for protective effects against oxidative stress induced by UV-B, IR-A or inflammation. A quantitative LC-MS study of FEPC shows that chlorogenic, caffeic and protocatechuic acids are the main phenolic compounds present, with concentrations of 15.6%, 15.3% and 4.8% of the total composition, respectively. With a validated analytical method, those compounds were quantified over different stages of the growing period. As for biological potential, first this extract demonstrates antioxidant and anti-inflammatory activities. Furthermore, ROS generation induced by IR-A and UV-B were strongly inhibited by A. nudicaulis extract, suggesting that Aralia nudicaulis L. rhizome extract could protect dermal cells against oxidative stress induced by UV-B and IR-A.

The Biological Activity of Monarda didyma L. Essential Oil and Its Effect as a Diet Supplement in Mice and Broiler Chicken.

The use of growth-promoting antibiotics in livestock faces increasing scrutiny and opposition due to concerns about the increased occurrence of antibiotic-resistant bacteria. Alternative solutions are being sought, and plants of Lamiaceae may provide an alternative to synthetic antibiotics in animal nutrition. In this study, we extracted essential oil from Monarda didyma, a member of the Lamiaceae family. We examined the chemical composition of the essential oil and then evaluated the antibacterial, antioxidant, and anti-inflammatory activities of M. didyma essential oil and its main compounds in vitro. We then evaluated the effectiveness of M. didyma essential oil in regard to growth performance, feed efficiency, and mortality in both mice and broilers. Carvacrol (49.03%) was the dominant compound in the essential oil extracts. M. didyma essential oil demonstrated antibacterial properties against Escherichia coli (MIC = 87 µg·mL-1), Staphylococcus aureus (MIC = 47 µg·mL-1), and Clostridium perfringens (MIC = 35 µg·mL-1). Supplementing the diet of mice with essential oil at a concentration of 0.1% significantly increased body weight (+5.4%) and feed efficiency (+18.85%). In broilers, M. didyma essential oil significantly improved body weight gain (2.64%). Our results suggest that adding M. didyma essential oil to the diet of broilers offers a potential substitute for antibiotic growth promoters.

Bio-Guided Fractionation of Retama raetam (Forssk.) Webb & Berthel Polar Extracts.

The fractionation of the methanolic extract (MeOH-E) of Retama raetam (Forssk.) Webb & Berthel and further analysis by thin layer chromatography resulted in four fractions (F1, F2, F3 and F4) that, in parallel with the MeOH-E, were screened for antioxidant, cytotoxic, antidiabetic and antibacterial properties. In addition, chemical characterization of their bioactive molecules was performed using LC-DAD-ESI/MSn. The results indicated that F3 was the most promising regarding antioxidant and cytotoxicity abilities, possibly due to its richness in flavonoids class, particularly isoflavones. In turn, F1 was characterized by the presence of the most polar compounds from MeOH-E (organic acids and piscidic acid) and showed promising abilities to inhibit α-amylase, while F4, which contained prenylated flavonoids and furanoflavonoids, was the most active against the tested bacteria. The gathered results emphasize the distinct biological potentials of purified fractions of Retama raetam.

On the role of the vinylsulfoxide side chain of dirchromone towards its bioactivities.

Analogs of dirchromone were prepared to shed light on the pivotal role of its peculiar vinylsulfoxide side chain towards its cytotoxic and antimicrobial properties, especially dependant upon the presence and oxidation state of sulfur. The reaction of dirchromone with cysteamine revealed a surprising Michael acceptor behavior with elimination of the methylsulfinyl moiety and redox transformation of the sulfur atom that could be involved in the mode of action of dirchromone within cells.

Pili Tree (Canarium ovatum) Resin's Antibacterial Essential Oil and Hydrosol as Rich Sources of (S)-Phellandrenes Derivatives.

Five batches of resin from the Pili tree (Canarium ovatum Engl.) were distilled, and their essential oils and hydrosols were analyzed by gas chromatography. The oils, obtained in yields of 13.4-19.7 % v/m, featured α-phellandrene in high proportions (50-65 %), alongside limonene, ß-phellandrene and para-cymene. Chiral GC analysis confirmed that both phellandrenes were in fact >95 % (S)-(+) enantiomers, while the other monoterpenes featured less pronounced enantiomeric excesses. The hydrosols were rich in α-phellandrene oxidation products including cis-α-phellandrene epoxide and a series of para-menth-5-ene-1,2-diol isomers. Both essential oils and hydrosols were tested for their antibacterial activity against Escherichia coli and Staphylococcus aureus and exhibited MIC90 of less than 5 and 0.5 mg/mL of total volatiles, respectively. The essential oil features some potential as a source of readily available natural (S)-(+)-α-phellandrene.

Dihydrochalcone Derivatives from Populus balsamifera L. Buds for the Treatment of Psoriasis.

Psoriasis is a skin disorder characterized by epidermal hyperplasia, hyperkeratosis, and inflammation. The treatments currently available on the market only improve patients' quality of life and are associated with undesirable side effects. Thus, research leading to the development of new, effective, and safer therapeutic agents is still relevant. Populus balsamifera L. buds were used traditionally by Native Americans to treat various skin pathologies such as eczema and psoriasis. In this study, the antipsoriatic activities of dihydrochalcone derivatives from Populus balsamifera L. buds, known as balsacones, were investigated. The experiments were performed in vitro using a psoriatic skin substitute model. Also, anti-inflammatory and antioxidant activities were investigated. The tested balsacones showed promising antipsoriatic properties by slowing down cell growth and by regulating the expression of involucrin, loricrin, and Ki67 better than methotrexate in psoriatic substitutes. All five tested compounds could be an effective topical treatment for psoriasis, with promising anti-inflammatory and antioxidant actions that may contribute to clinical improvement in patients with psoriasis.

Chemical composition and anti-herpes simplex virus type 1 (HSV-1) activity of extracts from Cornus canadensis.

BACKGROUND: Many plants of boreal forest of Quebec have been used by Native Americans to treat a variety of microbial infections. However, the antiviral activities of these plants have been seldom evaluated on cellular models to validate their in vitro efficiencies. In this study, Cornus canadensis L. (Cornaceae), a plant used in Native American traditional medicine to treat possible antiviral infections, has been selected for further examination. METHODS: The plant was extracted by decoction and infusion with water, water/ethanol 1:1 and ethanol to obtain extracts similar to those used by Native Americans. The effects of the extracts were tested on herpes simplex virus type-1 (HSV-1) using a plaque reduction assay. Moreover, bioassay-guided fractionation was achieved to isolate bioactive compounds. RESULTS: Water/ethanol 1:1 infusion of C. canadensis leaves were the most active extracts to inhibit virus absorption with EC50 of about 9 µg mL-1, whereas for direct mode, both extraction methods using water or water/ethanol 1:1 as solvent were relatively similar with EC50 ranging from 11 to 17 µg mL-1. The fractionation led to the identification of active fractions containing hydrolysable tannins. Tellimagrandin I was found the most active compound with an EC50 of 2.6 µM for the direct mode and 5.0 µM for the absorption mode. CONCLUSION: Altogether, the results presented in this work support the antiviral activity of Cornus canadensis used in Native American traditional medicine.

Structure elucidation of anti-methicillin resistant Staphylococcus aureus (MRSA) flavonoids from balsam poplar buds.

There is nowadays an urgent need for developing novel generations of antibiotic agents due to the increased resistance of pathogenic bacteria. As a rich reservoir of structurally diverse compounds, plant species hold promise in this regard. Within this framework, we isolated a unique series of antibacterial flavonoids, named balsacones N-U, featuring multiple cinnamyl chains on the flavan skeleton. The structures of these compounds, isolated as racemates, were determined using extensive 1D and 2D NMR analysis in tandem with HRMS. Balsacones N-U along with previously isolated balsacones A-M were evaluated for their antibacterial activity against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA). Several of the tested balsacones were potent anti-MRSA agents showing MIC values in the low micromolar range. Structure-activity relationships study highlighted some important parameters involved in the antibacterial activity of balsacones such as the presence of cinnamyl and cinnamoyl chains at the C-3 and C-8 positions of the flavan skeleton, respectively. These results suggest that balsacones could represent a potential novel class of naturally occurring anti-MRSA agents.

Dirchromones: Cytotoxic Organic Sulfur Compounds Isolated from Dirca palustris.

Eight novel organic sulfur compounds featuring an unprecedented structure among natural organosulfur molecules are reported. The identified compounds, named dirchromones (1-8), were isolated from a dichloromethane extract of the roots, bark, and wood of Dirca palustris, an endemic shrub of eastern North America. Their identification was based on thorough NMR, IR, and HRMS spectroscopic data interpretation. These compounds showed cytotoxic and mild Gram-positive antibacterial activities in vitro, while being inactive against Gram-negative Escherichia coli and the yeast Candida albicans. This is the first report of sulfur-containing compounds from a species of the Thymelaeaceae.

DFT Calculations and ROESY NMR Data for the Diastereochemical Characterization of Cytotoxic Tetraterpenoids from the Oleoresin of Abies balsamea.

Eight non-carotenoid tetraterpenoids, abibalsamins C-J (3-10), were isolated from the oleoresin of Abies balsamea. Their chemical structures were determined based on analysis of 1D/2D NMR and MS data. The assignment of their relative configurations was accomplished using homonuclear coupling constants in tandem with ROESY data. However, the presence of two stereogenic centers on a flexible side chain complicated the characterization. In silico models and ROESY data were analyzed in order to assign relative configurations of the isolated tetraterpenoids. Abibalsamins B and H-J showed moderate cytotoxicity against human A549 lung carcinoma cells, with IC50 values ranging between 6.7 and 10 µM.

Antibacterial Balsacones J-M, Hydroxycinnamoylated Dihydrochalcones from Populus balsamifera Buds.

A phytochemical investigation of buds from the hardwood tree Populus balsamifera led to the isolation of six new cinnamoylated dihydrochalcones as pairs of racemates and one as a racemic mixture along with the known compound iryantherin-D (2), the absolute configuration of which was determined for the first time. The structures of balsacones J (1), K (3), L (4), and M (5) were elucidated on the basis of spectroscopic data (1D and 2D NMR, IR, and MS). Chiral HPLC separations were carried out, and the absolute configuration of the isolated enantiomers unambiguously established via X-ray diffraction analyses and electron circular dichroism spectroscopic data. Each of the purified enantiomers exhibited potent in vitro antibacterial activity against Staphylococcus aureus with IC50 values ranging from 0.61 to 6 µM.

Diphoterine, an amphoteric rinsing solution, reduces hydrofluoric acid injuries in an ex vivo pigskin model.

Hydrofluoric acid (HF) is a ubiquitous industrial chemical that is particularly hazardous because of the potential for systemic effects and the induction of severe cutaneous necrosis after contact with the skin. Minimizing skin injury requires decontaminating the affected area promptly with an emergency rinsing solution. Few experimental studies have objectively characterized rinsing solutions such as Diphoterine (DP). Here we develop an ex vivo pigskin model to study and compare the efficacy of rinsing solutions as initial decontaminating agents to stop the progression of skin lesions after HF splashing. The pigskin model shows an immediate local response to HF at varying concentrations and exposure times. We then exposed the pigskin biopsies to 3.75% HF for 1 min and rinsed them with different solutions, including water, 0.9% NaCl solution (saline), 10% calcium gluconate (CaG), Hexafluorine (HXF), and DP. We found DP to be a more effective agent for decontaminating HF lesions than water, saline, and CaG. DP had a similar efficacy as HXF, an emergency rinsing solution used specifically for decontaminating HF-exposed skin. This study shows that skin exposed to HF must be treated quickly from the first minute of exposure.