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Aβ 1-42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC 50  = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aβ 1-42 and protect nerve cells, and it can also penetrate the blood-brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl 3 -induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Butin and butein are significant bioactive flavanones derived from plants, existing as tautomers of each other. However, their physicochemical attributes, such as their spectral profiles under varying experimental conditions in aqueous solutions and established chromatographic methods for distinguishing between them, remain undetermined. In this study, we determined the basic properties of butin and butein using conventional spectroscopic, reversed-phase, and chiral HPLC analyses. The spectra of the synthesized butin and butein were analyzed using a UV-Vis spectrophotometer in several solvents with different polarities as well as in aqueous solutions at various pH values. Furthermore, the behavior of the measured spectra was reproduced by calculations to reveal the effects of the solvent and pH on the spectra of butin and butein in organic and aqueous solutions. Subsequently, we assessed the structural stability of butin and butein using reversed-phase HPLC, which revealed that butein is unstable compared with butin in a general culture medium. The synthesized butin was effectively separated into R- and S-isomers with positive and negative Cotton effects, respectively, via HPLC using a chiral column. These findings will aid in uncovering the individual properties of both butin and butein that may have been concealed by their tautomerism and enable the synthesis of S-butin, which is typically challenging and time-consuming to isolate.

In this study, a series of naringenin- O -alkylamine derivatives were designed and obtained by introducing an alkylamine fragment into the naringenin skeleton. The in vitro biological activity results revealed that compounds 5f and 7k showed good antioxidant activity with ORAC values of 2.3 eq and 1.2 eq , respectively. Compounds 5f and 7k were reversible and excellent hu AChE inhibitors with IC 50 values of 0.91 μM and 0.57 μM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced A β 1-42 aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited hu AChE-A β 1-40 aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu 2+ -induced A β 1-42 aggregation with 73.5% and 68.7% inhibition rates, respectively. Furthermore, compounds 5f and 7k could cross the blood-brain barrier in vitro and displayed good neuroprotective effects and anti-inflammatory properties. Further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed a good hepatoprotective effect by its antioxidant activity. The in vivo study displayed that compound 5f significantly improved scopolamine-induced mice memory impairment. Therefore, compound 5f was a potential multifunctional candidate for the treatment of AD.

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC 50  = 9.7 μM) inhibitor. In addition, compound 3c significantly inhibited self-induced Aβ 1-42 aggregation, and it could activate UPS degradation pathway in HT22 cells and clear the aggregated proteins associated with AD. Moreover, compound 3c was a selective metal chelator, and it significantly inhibited and disaggregated Cu 2+ -mediated Aβ 1-42 aggregation. Furthermore, compound 3c displayed remarkable neuroprotective effect and anti-inflammatory property. Interestingly, compound 3c displayed good hepatoprotective effect by its antioxidant activity. More importantly, compound 3c demonstrated favourable blood-brain barrier penetration in vitro and drug-like property. Therefore, compound 3c was a promising multifunctional agent for the treatment of AD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Naringenin (NRG) is a natural flavonoid compound abundantly present in citrus fruits and has the potential to treat respiratory disorders. However, the clinical therapeutic effect of NRG is limited by its low bioavailability due to poor solubility. To enhance the solubility, naringenin nanosuspensions (NRG-NSps) were prepared by applying tocopherol polyethylene glycol succinate (TPGS) as the nanocarrier via the media-milling method. The particle size, morphology, and drug-loading content of NRG-NSps were examined, and the stability was evaluated by detecting particle size changes in different physiological media. NRG-NSps exhibited a flaky appearance with a mean diameter of 216.9 nm, and the drug-loading content was 66.7%. NRG-NSps exhibited good storage stability and media stability. NRG-NSps presented a sustainable release profile, and the cumulative drug-release rate approached approximately 95% within 7 d. NRG-NSps improved the antitussive effect significantly compared with the original NRG, the cough frequency was decreased from 22 to 15 times, and the cough incubation period was prolonged from 85.3 to 121.6 s. Besides, NRG-NSps also enhanced expectorant effects significantly, and phenol red secretion was increased from 1.02 to 1.45 μg/mL. These results indicate that NRG-NSps could enhance the bioavailability of NRG significantly and possess a potential clinical application.

12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO)., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Background: Resveratrol is a phenolic natural product, which is found in red grapes and in Japanese knotweed root (Polygonum cuspidatum). Naringenin is one of the flavonoid compounds found in landing grape and other citrus fruits. Both agents exert antioxidant and anti-inflammatory properties., Objective: In this study, the effect of Resveratrol and Naringenin in an in vitro model of retinoblastoma of the eye has been investigated., Methods: XTT and trypan blue assays were used to evaluate the anti-proliferative/cytotixic effect of resveratrol and naringenin in Y79 cells. With the aid of AnnexinV/PI flow cytometry, the kind of cell death was investigated. To assess important gene expression levels at mRNA level involved in apoptosis, Real-time PCR was utilized., Results: Naringenin and resveratrol significantly decreased proliferation and stimulated cell death (mostly apoptosis) in Y79 cells at 50 and 100 (μg/ml) after 24 and 48 hours. Additional cytotoxic effect was observed after 48 hours. Furthermore expression level of Bax and Bcl2 mRNAs altered significantly in all samples treated with 50 (μg/ml) of naringenin, resveratrol, or simultaneously with both. P21 mRNAs expression altered in all mentioned samples except those treated with 50 (μg/ml) of resveratrol., Conclusion: Based on the results, it can be concluded that resveratrol and naringenin can decrease cell viability in retinoblastoma cells in an in vitro dose/time-dependent manner. Albeit more studies are needed to shed the light on the mechanism of action, our data reveal a potential synergistic cytotoxic effect of naringenin and resveratrol on Y79 cells in 48 hours., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Pinocembrin is a dihydroflavonoid, which is widely found in several plant species. Although pinocembrin has good pharmacological activity, it has poor water solubility and low bioavailability. Therefore, we have modified the structure of pinocembrin with a combination of different amino acids to solve this problem. Moreover, the effect of the antiaging activity of them has not been explored. We aim to investigate the effect of pinocembrin and its amino acid derivatives on the aging of Caenorhabditis elegans ., Methods: Pinocembrin was spliced with different amino acids in order to obtain their corresponding derivatives. The preliminary research of pinocembrin and its amino acid derivatives on antiaging effect was studied by using the C. elegans model. Among all the compounds, the one shows the best antiaging effect was then studied on antiaging mechanism. The protective effect on nematodes under emergency conditions was explained by detecting the ROS content and sod-3p::GFP fusion protein expression in nematodes; the possible anti-aging mechanism of nematodes was determined by DAF-16 nuclear localization experiment and the survival curve of transgenic nematodes model under stress conditions., Results: Pb-3 showed the best effect on increasing tolerance to thermal and oxidative stress and reduce the accumulation of lipofuscin. In the assay of C. elegans , pb-3 reduced intracellular ROS accumulation. Application of pb-3 to the transgenic mutant TJ356 induced the translocation of the transcription factor DAF-16 from the cytosol to the nucleus, and modulated the expression of SOD-3 (downstream genes of daf-16 ), which regulates longevity in C. elegans . Moreover, pb-3 did not prolong the lifespan of daf-16, age-1, daf-2 and hsp16.2 mutants, suggesting that these genetic pathways are involved in mediating the antiaging effects of pb-3 ., Conclusion: The antioxidant and antiaging properties of pb-3 may involve in the DAF-16/FOXO transcription process. Pinocembrin amino acid derivatives might be a novel agent for antiaging therapy., Competing Interests: The authors declare no conflict of interest., (© 2021 Wang et al.)

Malignant tumor is a disease with high mortality. Traditional treatment methods have many disadvantages, such as side-effects, drug resistance. Because cyclin-dependent kinase 1 (CDK1) plays an indispensable role in cell cycle regulation, it became an attractive target in rational anti-cancer drug discovery. Herein, we reported a series of baicalein derivatives, which remarkably repressed the proliferation of MCF-7 tumor cells and the activity of CDK1/cyclin B kinase. Among them, compound 4a displayed better inhibition rate than flavopiridol against MCF-7 proliferation at the concentration of 50 μg/ml, comparable to compound CGP74514A, while compound 3o possessed the best activity against CDK1/cyclin B kinase (IC 50  = 1.26 μM). The inhibitory activities toward the kinase well correlated with anti-proliferative activities. Molecular docking results suggested that compound 3o can interact with the key amino acid residues, E81, L83, and D146, of CDK1 through hydrogen bond just like flavopiridol does. And it can also form an extra hydrogen bond with D146 by its introduced 7-acrylate group, which flavopiridol does not have. These findings proved that baicalein derivatives can be used as CDK1 inhibitors fighting against cancer., (© 2021 John Wiley & Sons Ltd.)

A series of naringenin derivatives were designed and synthesized as multifunctional anti-Alzheimer's disease (AD) agents. The results showed that these derivatives displayed moderate-to-good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities at the micromolar range (IC 50 , 12.91 ~ 62.52 μM for AChE and 0.094 ~ 13.72 μM for BuChE). Specifically, compound 1 showed the highest inhibitory activity against BuChE with the IC 50 value of (0.094 ± 0.0054) μM. A Lineweaver-Burk plot and molecular docking studies demonstrated that 1 targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of BuChE. Besides, all derivatives showed excellent hydroxyl free radicals (·OH) scavenging ability than vitamin C and cyclic voltammetry results displayed that 1 could effectively scavenge superoxide anion radical (·O 2 - ). In addition, compound 1 displayed good metal chelating properties and had anti-Aβ aggregation activities. Therefore, compound 1 might be the potential anti-AD agent for further developments., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The molecular hybridization concept led us to design a series of galloyl conjugates of flavanones that have potent osteoblast differentiation ability in vitro and promote bone formation in vivo . An array of in vitro studies, especially gene expression of osteogenic markers, evinced compound 5e as the most potent bone anabolic agent, found to be active at 1 pM, which was then further assessed for its osteogenic potential in vivo . From in vivo studies on rat calvaria and a fracture defect model, we inferred that compound 5e , at an oral dose of 5 mg/(kg day), increased the expression of osteogenic genes (RUNX2, BMP-2, Col1, and OCN) and the bone formation rate and significantly promoted bone regeneration at the fracture site, as evidenced by the increased bone volume/tissue fraction compared with vehicle-treated rats. Furthermore, structure-activity relationship studies and pharmacokinetic studies suggest 5e as a potential bone anabolic lead for future osteoporosis drug development.

Renal Cell Carcinoma (RCC) is on the top 10 of the most incident cancers worldwide, being a third of patients diagnosed with advanced disease, for which no curative therapies are currently available. Thus, new effective therapeutic strategies are urgently needed. Herein, we tested the antineoplastic effect of newly synthesized 3-nitroflavanones (MLo1302) on RCC cell lines. 786-O, Caki2, and ACHN cell lines were cultured and treated with newly synthesized 3-nitroflavanones. IC50 values were calculated based on the effect on cell viability assessed by MTT assay, after 72 h of exposure. MLo1302 displayed antineoplastic properties in RCC cell lines through marked reduction of cell viability, increased apoptosis and DNA damage, and morphometric alterations indicating a less aggressive phenotype. MLo1302 induced a significant reduction of global DNA methylation and DNMT mRNA levels, increasing global DNA hydroxymethylation and TET expression. Moreover, MLo1302 decreased DNMT3A activity in RCC cell lines, demethylated and re-expressed hypermethylated genes in CAM-generated tumors. A marked in vivo decrease in tumor growth and angiogenesis was also disclosed. MLo1302 disclosed antineoplastic and demethylating activity in RCC cell lines, constituting a potential therapeutic agent for RCC patients., (Copyright © 2021. Published by Elsevier Masson SAS.)

The present work describes the systematic development of paclitaxel and naringenin-loaded solid lipid nanoparticles (SLNs) for the treatment of glioblastoma multiforme (GBM). So far only temozolomide therapy is available for the GBM treatment, which fails by large amount due to poor brain permeability of the drug and recurrent metastasis of the tumor. Thus, we investigated the drug combination containing paclitaxel and naringenin for the treatment of GBM, as these drugs have individually demonstrated significant potential for the management of a wide variety of carcinoma. A systematic product development approach was adopted where risk assessment was performed for evaluating the impact of various formulation and process parameters on the quality attributes of the SLNs. I-optimal response surface design was employed for optimization of the dual drug-loaded SLNs prepared by micro-emulsification method, where Percirol ATO5 and Dynasan 114 were used as the solid lipid and surfactant, while Lutrol F188 was used as the stabilizer. Drug loaded-SLNs were subjected to detailed in vitro and in vivo characterization studies. Cyclic RGD peptide sequence (Arg-Gly-Asp) was added to the formulation to obtain the surface modified SLNs which were also evaluated for the particle size and surface charge. The optimized drug-loaded SLNs exhibited particle size and surface charge of 129 nm and 23 mV, drug entrapment efficiency >80% and drug loading efficiency >7%. In vitro drug release study carried out by micro dialysis bag method indicated more than 70% drug was release observed within 8 h time period. In vivo pharmacokinetic evaluation showed significant improvement (p < 0.05) in drug absorption parameters (C max and AUC) from the optimized SLNs over the free drug suspension. Cytotoxicity evaluation on U87MG glioma cells indicated SLNs with higher cytotoxicity as compared to that of the free drug suspension (p < 0.05). Evaluation of uptake by florescence measurement indicated superior uptake of SLNs tagged with dye over the plain dye solution. Overall, the dual drug-loaded SLNs showed better chemoprotective effect over the plain drug solution, thus construed superior anticancer activity of the developed nanoformulation in the management of glioblastoma multiforme., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Wound healing represents an urgent need from the clinical point of view. Several diseases result in wound conditions which are difficult to treat, such as in the case of diabetic foot ulcer. Starting from there, the medicinal research has focused on various targets over the years, including GPCRs as new wound healing drug targets. In line with this, GPR120, known to be an attractive target in type 2 diabetes drug discovery, was studied to finalize the development of new wound healing agents. Pinocembrin (HW0) was evaluated as a suitable compound for interacting with GPR120, and was hybridized with fatty acids, which are known endogenous GPR120 ligands, to enhance the wound healing potential and GPR120 interactions. HW0 and its 7-linolenoyl derivative (HW3) were found to be innovative wound healing agents. Immunofluorescence and functional assays suggested that their activity was mediated by GPR120, and docking simulations showed that the compounds could share the same pocket occupied by the known GPR120 agonist, TUG-891., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The bis-Schiff base of N,N'-1,10-bis(naringin) triethylenetetraamine (1) was prepared, as a copper(II) ion chelator, compound 1 was used for Alzheimer's disease therapy in vitro. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of compound 1 showed that this Schiff base could promote PC12 cells proliferation, and also, compound 1 could inhibit Cu 2+ -amyloid-β (Aβ) 1-42 mediated cytotoxicity on PC12 cells. The thioflavine T (ThT) assay showed that 1 can effectively attenuate Cu 2+ -induced Aβ 1-42 aggregation. In addition, compound 1 is determined to be potent antioxidants on the basis of in vitro antioxidant assay, it can effectively decease the level of reactive oxygen species (ROS) in Cu 2+ -Aβ 1-42 -treated PC12 cells and elevate the superoxide dismutase (SOD) activity in Cu 2+ -Aβ 1-42 -treated PC12 cells. The results show that N,N'-1,10-bis(naringin) triethylenetetraamine is a potential agent for therapy of Alzheimer's disease.

Background: Nuclear Factor-kappa B (NF-κB) is usually activated in Wilms Tumor (WT) cells and plays a critical role in WT development., Objective: The study's purpose was to screen for a NF-κB inhibitor from the natural product library and explore its effects on WT development., Methods: Luciferase assay was employed to assess the effects of natural chemicals on NF-κB activity. CCK-8 assay was conducted to assess cell growth in response to naringenin. WT xenograft model was established to analyze the effect of naringenin in vivo. Quantitative real-time PCR and Western blot were performed to examine the mRNA and protein levels of relative genes, respectively., Results: Naringenin displayed a significant inhibitory effect on NF-κB activation in SK-NEP-1 cells. In SKNEP- 1 and G-401 cells, naringenin inhibited p65 phosphorylation. Moreover, naringenin suppressed TNF-α- induced p65 phosphorylation in WT cells. Naringenin inhibited TLR4 expression at both mRNA and protein levels in WT cells. CCK-8 staining showed that naringenin inhibited cell growth of the two above WT cells in doseand time-dependent manner, whereas Toll-Like Receptor 4 (TLR4) overexpression partially reversed the above phenomena. Besides, naringenin suppressed WT tumor growth in a dose- and time-dependent manner in vivo. Western blot found that naringenin inhibited TLR4 expression and p65 phosphorylation in WT xenograft tumors., Conclusion: Naringenin inhibits WT development via suppressing TLR4/NF-κB signaling., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The isomers 8-prenylnaringenin and 6-prenylnaringenin, both secondary metabolites occurring in hops, show interesting biological effects, like estrogen-like, cytotoxic, or neuro regenerative activities. Accordingly, abundant sources for this special flavonoids are needed. Extraction is not recommended due to the very low amounts present in plants and different synthesis approaches are characterized by modest yields, multiple steps, the use of expensive chemicals, or an elaborate synthesis. An easy synthesis strategy is the demethylation of xanthohumol, which is available due to hop extraction industry, using lithium chloride and dimethylformamide, but byproducts and low yield did not make this feasible until now. In this study, the demethylation of xanthohumol to 8-prenylnaringenin and 6-prenylnaringenin is described the first time and this reaction was optimized using Design of Experiment and microwave irradiation. With the optimized conditions-temperature 198 °C, 55 eq. lithium chloride, and a reaction time of 9 min, a final yield of 76% of both prenylated flavonoids is reached.

New antimicrobial agents are needed to address infections caused by multidrug-resistant bacteria. Here, we are reporting novel O -alkyl derivatives of naringenin and their oximes, including novel compounds with a naringenin core and O -hexyl chains, showing activity against clinical strains of clarithromycin-resistant Helicobacter pylori , vancomycin-resistant Enterococcus faecalis , methicillin-resistant Staphylococcus aureus , and beta-lactam-resistant Acinetobacter baumannii and Klebsiella pneumoniae. The minimum inhibitory concentrations (MICs), which provide a quantitative measure of antimicrobial activity, were in the low microgram range for the selected compounds. Checkerboard assays for the most active compounds in combination with antibiotics revealed interactions that varied from synergistic to neutral.

Fluorophores with aggregation-induced emission enhancement (AIEE) characteristics applied in bioimaging have attracted more and more attention in recent years. In this work, a series of flavanone compounds with AIEE characteristics was developed and applied to fluorescence imaging of mitochondria and zebrafish. The compounds were readily prepared by the thermal dehydration of chalcone that was obtained by the reaction of o -hydroxyacetophenone and benzaldehyde. Two of these compounds showed significant AIEE characteristics by fluorescence performance experiments, including optical spectra, fluorescence spectra, fluorescence quantum yield (φ F ), fluorescence lifetime, and scanning electron microscopy (SEM). Compared with traditional organic fluorescent dyes, these compounds have high fluorescence emission and high fluorescence quantum yield in solid or aggregated state, which overcomes the shortcoming of aggregation-caused quenching (ACQ). More importantly, the two compounds exhibited low cytotoxicity and good cytocompatibility in A549 lung cells at the experimental concentration range and they specifically targeted mitochondria, which make it of great potential use in mitochondria labeling. In addition, they were embryonic membrane permeable and had different affinities for different tissues and organs of zebrafish, but mainly distributed in the digestive system, providing a basis for the application of such compounds in bioimaging. These AIEE compounds with superior properties could be of great potential use in mitochondria imaging and other in vivo studies.

This study aimed to develop a procedure for preparing a modified silica-naringin hybrid system. To accomplish, the properties of the obtained material were characterized by FT-IR analysis, UV-Vis spectrophotometry, thermogravimetry, scanning electron microscopy (SEM), and zeta potential. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to characterize and evaluate the antioxidant activity. The naringin release profile at pH = 1.2 and 7.2 were determined. FT-IR studies confirmed the interaction between the naringin and present carrier. The release study indicated that a release an approximately 20% and 50% of the release occurred in the first 30 min in pH = 1.2 and 7.2, respectively. The thermogravimetry and UV-Vis spectrophotometry analysis allowed us to determine the amount of naringin in the studied hybrid material at the level of several percent. The proposed hybrid material shows good stability, as evidenced by the zeta potential of about +30 and -30 mV in an acidic and alkaline environment, respectively. Antioxidant properties are comparable to those of pure naringin. The results suggest that the obtained hybrid material is a promising product with antioxidant properties.

Prenylated flavanones are polyphenols that have diverse biological properties. The present paper focuses on a HPLC method validation for the quantification of prenylated flavanones (2 S )-5,7-dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1Benzopyran-4-one 1 and derivatives (2 S )-5,7-bis(acetyloxy)-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one A ; (2 S )-5-hydroxy-7-methoxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one B ; (8 S )-5-hydroxy-2,2-dimethyl-8-phenyl-3,4,7,8-tetrahydro-2H,6H-Benzo[1,2-b:5,4-b']dipyran-6-one C ; and (8 S )-5-hydroxy-2,2-dimethyl-8-phenyl-7,8-dihydro-2H,6H-Benzo[1,2-b:5,4-b']dipyran-6-one D applied in biopharmaceutic studies. The linear relationships are proven with significant correlation coefficients (R 2 ˃ 0.999) in the range of 1.56 to 200 μg/mL with low limits of detection and quantification, on average of 0.4 μg/mL and 1.2 μg/mL, respectively. The validation method used in this work is highly accurate and precise, with values lower than 15%. The relative standard deviation values of repeatability of the instrumental system are demonstrated with less than 0.6% for all studied flavanones. Therefore, the applicability method of the quantification of the prenylated flavanones was established using the permeation of human skin in the Franz cell system. During the method previously described, there was no interference observed from human skin components in ex vivo permeation studies.

Chagas disease, also known as American trypanosomiasis, is classified as a neglected disease by the World Health Organization. For clinical treatment, only two drugs have been on the market, Benznidazole and Nifurtimox, both of which are recommended for use in the acute phase but present low cure rates in the chronic phase. Furthermore, strong side effects may result in discontinuation of this treatment. Faced with this situation, we report the synthesis and trypanocidal activity of 3-benzoyl-flavanones. Novel 3-benzoyl-flavanone derivatives were prepared in satisfactory yields in the 3-step synthetic procedure. According to recommended guidelines, the whole cell-based screening methodology was utilized that allowed for the simultaneous use of both parasite forms responsible for human infection. The majority of the tested compounds displayed promising anti- Trypanosoma cruzi activity and the most potent flavanone bearing a nitrofuran moiety was more potent than the reference drug, Benznidazole.

Synthetic flavonoids containing a naphthalene ring have attracted attention as potential cytotoxic compounds. Here, we synthesized ten chalcones and their corresponding flavanones and evaluated their antiproliferative activity against the human tumour cell line U-937. This series of chalcone derivatives was characterized by the presence of a naphthalene ring which was kept unaltered- and attached to the β carbon of the 1-phenyl-2-propen-1-one framework. The structure-activity relationship of these chalcone derivatives and their corresponding cyclic compounds was investigated by the introduction of different substituents (methyl, methoxy, benzyloxy, chlorine) or by varying the position of the methoxy or benzyloxy groups on the A ring. The results revealed that both the chalcone containing the methoxy group at 5' position of the A ring as well as its corresponding flavanone [6-methoxy-2-(naphthalen-1-yl)chroman-4-one] were the most cytotoxic compounds, with IC 50 values of 2.8 ± 0.2 and 1.3 ± 0.2 μM, respectively, against U-937 cells. This synthetic flavanone was as cytotoxic as the antitumor etoposide in U-937 cells and displayed strong cytotoxicity against additional human leukaemia cell lines, including HL-60, MOLT-3 and NALM-6. Human peripheral blood mononuclear cells were more resistant than leukaemia cells to the cytotoxic effects of the flavanone. Treatment of U-937 cells with this compound induced G 2 -M cell cycle arrest, an increase in sub-G 1 ratio and annexin-V positive cells, mitochondrial cytochrome c release, caspase activation and poly(ADP-ribose)polymerase processing. Apoptosis induction triggered by this flavonoid was blocked by overexpression of the anti-apoptotic protein Bcl-2. This flavanone induces phosphorylation of p38 mitogen-activated protein kinases, extracellular-signal regulated kinases and c-jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) following different kinetics. Moreover, cell death was attenuated by the inhibition of mitogen-activated extracellular kinases and JNK/SAPK and was independent of reactive oxygen species generation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Onychine is a 4-azafluorenone alkaloid isolated from the Annonaceae family, in low concentrations. Onychine and its analogs exhibit a wide range of pharmacological activities such as antifungal, antibacterial, anticancer, and antimalarial. Because of the high bioactivity of some 4-azafluorenone derivatives, several synthetic methods have been developed for their procurement., Objective: Considering the importance of these alkaloids, we aim to present the main synthetic approaches to onychines and its derivatives and the biological activity of some 4-azafluorenones., Methods: The most prominent methodologies for the synthesis of onychines were reviewed., Results: In this work, we cover many synthetic approaches for the synthesis of onychine and 4-azafluorenone derivatives including intramolecular cyclizations, multicomponent reactions, microwave-assisted multicomponent reactions, Diels-alder reactions, among others. Moreover, we also review the biological activity of 4-azafluorenones., Conclusion: 4-azafluorenones have risen as prominent structures in medicinal chemistry; however, most of the time, access to new derivatives involves toxic catalysts, harsh reaction conditions, and long-step procedures. Therefore, the development of new synthetic routes with more operational simplicity, simple purification procedure, good yields, and low environmental impact, is desirable., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The burst release of active osteogenic factors, which is not beneficial to osteogenesis, is commonly encountered in bone tissue engineering. The aims of this study were to prepare naringin-loaded microsphere/sucrose acetate isobutyrate (Ng-m-SAIB) hybrid depots, reduce the burst release of naringin (Ng), and improve osteogenesis. The morphology and size distributions of electrosprayed Ng-microspheres were characterized by scanning electron microscopy (SEM). The Ng-microspheres and Ng-m-SAIB depots were characterized by Fourier transform infrared spectroscopy (FTIR) and in vitro release studies. In vitro osteoblast-microsphere interactions and in vivo osteogenesis were assessed after implantation of Ng-m-SAIB depots. The addition of sucrose acetate isobutyrate (SAIB) to monodisperse Ng-microspheres did not cause a change in the chemical structure. The performances of the microspheres in osteoblast-microsphere interactions were better when the naringin content was 4% than when it was at 2% and 6%. On the first day following the loading of Ng-microspheres (2%, 4%, and 6%) into SAIB depots, the burst release was reduced dramatically from 70.9% to 6.3%, 73.1% to 7.2%, and 73.9% to 9.9%, respectively. In addition, after 8 weeks, the new bone formation rate in the calvarial defects of SD rats receiving Ng-m-SAIB was 53.1% compared to 21.2% for the control group and 16.1% for the microsphere-SAIB group. These results demonstrated that Ng-m-SAIB hybrid depots may have promise in bone regeneration applications.

Baicalein, a famously effective component of the traditional Chinese medicine Rhizoma Huang Qin ( Scutellaria altissima L.), has been proved to have potent neuroprotection and anti-platelet aggregation effects with few side effects. Meanwhile, recent studies have revealed that the introduction of amino acid to baicalein could improve its neuroprotective activity. In the present study, a series of novel baicalein amino acid derivatives were designed, synthesized, and screened for their neuroprotective effect against tert -butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells and toxicity on the normal H9C2 cell line by standard methylthiazol tetrazolium (MTT) assay. In addition, all of the newly synthesized compounds were characterized by 1 H-NMR, 13 C-NMR, and high resolution mass spectrometry (HR-MS). The results showed that most of the compounds provided more potent neuroprotection than baicalein, and were equivalent to the positive drug edaravin. They showed no obvious cytotoxicity on normal H9C2 cells. Notably, the most active compound 8 displayed the highest protective effect (50% effective concentration (EC 50 ) = 4.31 μM) against tert -butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells, which was much better than the baicalein (EC 50 = 24.77 μM) and edaravin (EC 50 = 5.62 μM). Further research on the chick chorioallantoic membrane (CAM) model indicated that compound 8 could significantly increase angiogenesis, which might promote neurovascular proliferation. The detection of apoptosis analysis showed that compound 8 could dramatically alleviate morphological manifestations of cell damage. Moreover, the benzyloxycarbonyl (cbz)-protected baicalein amino acid derivatives showed better neuroprotective activity than the t -Butyloxy carbonyl (boc)-protected derivatives.

Wogonin, a natural product isolated from the plant Scutellaria baicalensis, has been shown to be a potent and selective inhibitor of CDK9. With the purpose of investigating the activity and selectivity of this chemical scaffold, several series of wogonin derivatives were prepared and screened for CDK9 inhibition and cellular antiproliferative activity. Among these compounds, the drug-like compound 51 showed potent activity against CDK9 (IC 50  = 19.9 nM) and MV4-11 cell growth (IC 50  = 20 nM). In addition, compound 51 showed much improved physicochemical properties, such as water solubility, compared with the parent compound wogonin. The follow-up studies showed that the compound 51 is selective toward CDK9-overexpressing cancer cells over normal cells. Preliminary mechanism studies on the anticancer effect indicated that 51 inhibited the proliferation of MV4-11 cells via caspase-dependent apoptosis. In addition, highlighted compound 51 showed significant antitumor activity in mouse acute myeloid leukemia (AML) models without producing apparent toxic effects in vivo, which gave us a new tool for further investigation of CDK9-targeted inhibitor as a potential antitumor drug especially for AML., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

A total of 47 flavanones were expediently synthesized via one-pot β-arylation of chromanones, a class of simple ketones possessing chemically unactivated β sites, with arylboronic acids via tandem palladium(II) catalysis. This reaction provides a novel route to various flavanones, including natural products such as naringenin trimethyl ether, in yields up to 92%.

Thymic stromal lymphopoietin (TSLP) plays an important role in the differentiation and proliferation of Th2 cells, resulting in eosinophilic inflammation and numerous allergic diseases. Baicalein (1), a major component of Scutellaria baicalensis, was found to be the first small molecule to block TSLP signaling pathways. It inhibited effectively eosinophil infiltration in house dust mite-induced and ovalbumin-challenged mouse models. Structure-activity relationship studies identified compound 11a, a biphenyl flavanone analog, as a novel human TSLP inhibitor for the discovery and development of new anti-allergic drugs.

Baicalein, an isolate of secutellaria baicalensis is known for its anti-inflammatory activity. In the present study, 12-triazole derivatives of baicalein were synthesized and evaluated against RSV infected BEAS-2B cells in vitro and in mice model in vivo. The preventive effect of most active compound 5f against RSV infection was studied in detail. The compound 5f treatment increased IFN-β1 expression in BEAS-2B cells infected with RSV. In BEAS-2B cells treatment with compound 5f inhibited RSV-induced secretion of interleukin-6 and -8 cytokines. It decreased RSV-induced nitric oxide & malondialdehyde production and inhibited the RSV-mediated activation of NF-κB, COX-2, Stat3 and MAPK. The p38 phosphorylation was enhanced significantly in RSV infected cells by compound 5f pre-treatment. RT-qPCR showed that compound 5f treatment of the RSV-infected mice significantly (P < 0.05) decreased viral load through reduction in the viral replication. In the mice model of RSV-infection compound 5f treatment decreased interleukin-6, -8 and tumor necrosis factor-α expression. The level of MPO, nitric oxide and malondialdehyde was also decreased significantly by compound 5f in the RSV infected mice BALF. It also reduced the infiltration of neutrophils and lymphocytes in the BALF of RVS-infected mice. In summary, compound 5f inhibits RSV-infection and prevents pulmonary airway inflammation through the activation of IFN signalling pathway., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Naringenin is one of the most abundant dietary flavonoids exerting several beneficial biological activities. Synthetic modification of naringenin is of continuous interest. During this study our aim was to synthesize a compound library of oxime and oxime ether derivatives of naringenin, and to investigate their biological activities. Two oximes and five oxime ether derivatives were prepared; their structure has been elucidated by NMR and high-resolution mass spectroscopy. The antiproliferative activity of the prepared compounds was evaluated by MTT assay against human leukemia (HL-60) and gynecological cancer cell lines isolated from cervical (HeLa, Siha) and breast (MCF-7, MDA-MB-231) cancers. Tert -butyl oxime ether derivative exerted the most potent cell growth inhibitory activity. Moreover, cell cycle analysis suggested that this derivative caused a significant increase in the hypodiploid (subG1) phase and induced apoptosis in Hela and Siha cells, and induced cell cycle arrest at G2/M phase in MCF-7 cells. The proapoptotic potential of the selected compound was confirmed by the activation of caspase-3. Antioxidant activities of the prepared molecules were also evaluated with xanthine oxidase, DPPH and ORAC assays, and the methyl substituted oxime ether exerted the most promising activity.

In our investigation, we concentrated on naringenin ( NG )-a widely studied flavanone that occurs in citrus fruits. As a result of a reaction with a range of alkyl iodides, 7 novel O -alkyl derivatives of naringenin ( 7a ⁻ 11a , 13a , 17a ) were obtained. Another chemical modification led to 9 oximes of O -alkyl naringenin derivatives ( 7b ⁻ 13b , 16b ⁻ 17b ) that were never described before. The obtained compounds were evaluated for their potential antibacterial activity against Escherichia coli , Staphylococcus aureus , and Bacillus subtilis . The results were reported as the standard minimal inhibitory concentration (MIC) values and compared with naringenin and its known O -alkyl derivatives. Compounds 4a , 10a , 12a , 14a , 4b , 10b , 11b , and 14b were described with MIC of 25 µg/mL or lower. The strongest bacteriostatic activity was observed for 7- O -butylnaringenin ( 12a ) against S. aureus (MIC = 6.25 µg/mL). Moreover, the antitumor effect of flavonoids was examined on human colon cancer cell line HT-29. Twenty-six compounds were characterized as possessing an antiproliferative activity stronger than that of naringenin. The replacement of the carbonyl group with an oxime moiety significantly increased the anticancer properties. The IC 50 values below 5 µg/mL were demonstrated for four oxime derivatives ( 8b , 11b , 13b and 16b ).

Background: Chemotherapeutic drugs have high toxicity associated with undesirable side-effects. Now, natural products are the most important anti-cancer agents because of their low toxicity and potential effectiveness., Methods: The half maximal inhibitory concentration (IC50) of amygdalin, naringenin and ellagic acid against breast, colon, and liver cell lines was estimated. The antimutagenic, free radical-, superoxide radical-, and hydroxyl radical- scavenging activities of these phytochemicals were measured. The expression of p53, bid, bax, bcl2, and caspases 9, 3, and 7 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in breast and liver cells. In addition, the active Caspase 3 protein was estimated in liver cells., Results: Ellagic acid showed the highest antioxidant and antiproliferative activities. Amygdalin and naringenin with low and moderate antioxidant profiles showed a corresponding low and moderate cytotoxicity against cancer cell lines, respectively. Naringenin and ellagic acid had a significant antimutagenic activity which was detected by the Salmonella test. Ellagic acid offered a much better antimutagenic activity than naringenin. The apoptotic pathway evoked by ellagic acid in HepG2 and MCF-7 cells was investigated. The results showed that a caspase-dependent and a caspase-independent apoptosis occurred in MCF-7 and HepG2, respectively., Conclusion: The antimutagenic/antioxidant properties are well correlated with the antiproliferative activity of the phytochemicals investigated. This study proved that some easy, quick and cheap assays could predict the antiproliferative activity of many nutraceuticals. Finally, this platform could help in the discovery of new anticancer agents where hundreds of compounds are investigated in the pipeline of drug discovery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Wogonin is a natural product isolated from the Scutellaria baicalensis and has been proved to be a potent and selective inhibitor of CDK9. Using this scaffold, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) targeting CDK9 by recruiting ubiquitin E3 ligase cereblon (CRBN). For constructing diverse Wogonin-based PROTACs, a "click chemistry" approach was employed for the synthesis of CDK9-targeting PROTACs. The results of western blotting assays showed that compounds containing triazole group in the linker could selectively downregulate the intracellular CDK9 level. Among these compounds, 11c could selectively degrade CDK9 in a concentration-dependent manner. In addition, the application of the proteasome inhibitor MG132 and CRBN siRNA silencing confirmed that 11c could promote the proteasome-dependent and CRBN-dependent degradation. Consistent with the degradation of the CDK9 protein, 11c selectively inhibits proliferation of CDK9-overexpressed cancer cells. Thus, our Wogonin-based PROTAC would be an efficient probe that induces the degradation of CDK9., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Naringenin is a naturally occurring flavonoid and due to its broad spectrum of biological activities, including anticancer properties, has attracted scientific attention in recent years. To contribute to these studies, we synthesized some new (±)-naringenin cyclic aminoethyl derivatives, analyzed the cytotoxic and anti-proliferative properties of them via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and mitochondrial apoptosis signaling response and gene expressions belong to caspase-3 depended apoptosis as biomarkers in both healthy and cancer cell lines. Our results suggest that some of our naringenin derivatives are potential anticancer agents with a selective death potential and targeting properties for mitochondrial apoptosis signaling against at least human cervix and breast cancer., (© 2018 Wiley-VHCA AG, Zurich, Switzerland.)

Phenotypic screening of high quality compound library is one of the most effective strategy to obtain novel bioactive compounds. Recently, our group have constructed a Wogonin-scaffold library with substituents diversity and successfully obtained a series of potent compounds. Herein, we reported the synthesis of these compounds and evaluated the in vitro antitumor activity against a panel of human tumor cell lines. Most of them showed good activity with a broad spectrum and preliminary structure-activity relationship for the substitutions were obtained. Further biological assays showed that the most potent compounds 18n and 20b could significantly enhance the intracellular ROS level and induce the cell apoptosis at low micromole level. Through similarity searching, CDK9 was identified as the potential target for 20b, which could be a start point for next structure-based drug design., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: The current standard-of-care antiplatelet therapy in cardiovascular disease patients is consisted of cyclooxygenase-1 (COX-1) inhibitor aspirin, along with a platelet receptor P2Y 12 antagonist. Recently, the triple antiplatelet therapy with aspirin, a P2Y 12 receptor antagonist and a protease activated receptor-1 (PAR-1) antagonist, has been suggested for the secondary prevention of atherothrombotic events, however presented an increased risk of bleeding. Therefore, the quest for novel antiplatelet agents simultaneously targeting the three pathways with improved efficacy/safety profile is of immense importance. Flavonoids as pre-validated ligands for numerous targets could serve as scaffolds targeting the three platelet activation pathways., Methods: Computational methods, Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) plasma stability and in vitro platelet aggregation experiments were used to establish the antiplatelet activity of the flavonoid naringenin and its conjugates., Results: In silico studies indicated that naringenin could bear a potent triple antiplatelet activity by inhibiting different platelet aggregation mechanisms. However, we found that in human platelets naringenin has diminished activity. We rationally designed and synthesized different naringenin conjugates aiming to amplify the antiplatelet activity of the parent compound. UHPLC-MS/MS revealed a slow degradation rate for a docosahexaenoic acid (DHA) - naringenin conjugate in human plasma. The antiplatelet profile of the new analogues was evaluated against in vitro platelet aggregation induced by several platelet agonists., Conclusions: The DHA - naringenin hybrid presented triple antiplatelet activity simultaneously targeting PAR-1, P2Y 12 and COX-1 platelet activation pathways., General Significance: Natural products could offer a rich source for novel bioactives as a powerful alternative to the current combinatorial use of three different antiplatelet drugs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The combination of berberine and baicalein may have a better therapeutic effect against disease. To explore the combined effect of baicalein and berberine in the treatment of obesity, we designed and synthesized a hybrid compound, and its biological activities were evaluated in 3T3-L1 adipocytes. The structures of the berberine-baicalein (BBS) compounds were confirmed by 1 H NMR, 13 C NMR, ultraviolet spectroscopy and high resolution mass spectrometry (HRMS). The present study showed that the IC 50 values of the inhibitory effects of baicalein, berberine and BBS against 3T3-L1 cells were 29.81±0.90, 21.84±1.67 and 9.42±0.60µM, respectively. The expression of mRNAs related to lipolysis and lipogenesis were examined by quantitative real-time PCR. The results showed that BBS could up-regulate the expression of the Atgl gene and down-regulate the mRNA expression of Srebp-1c, Fasn, Scd1, and Acc in 3T3-L1 adipocytes. These results indicate that BBS may have a stronger effect than baicalein and berberine on the viability of 3T3-L1 preadipocytes. In addition, BBS may have therapeutic effects and pharmacological activities against obesity. This "medicine couple" may be beneficial for studies of traditional Chinese medicine., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

O -Alkyl derivatives of naringenin ( 1a - 10a ) were prepared from naringenin using the corresponding alkyl iodides and anhydrous potassium carbonate. The resulting products were used to obtain oximes ( 1b - 10b ). All compounds were tested for antimicrobial activity against Escherichia coli ATCC10536, Staphylococcus aureus DSM799, Candida albicans DSM1386, Alternaria alternata CBS1526, Fusarium linii KB-F1, and Aspergillus niger DSM1957. The resulting biological activity was expressed as the increase in optical density (&#916;OD). The highest inhibitory effect against E. coli ATCC10536 was observed for 7,4'-di- O -pentylnaringenin ( 8a ), 7- O -dodecylnaringenin ( 9a ), naringenin oxime ( NG-OX ), 7,4'-di- O -pentylnaringenin oxime ( 8b ), and 7- O -dodecylnaringenin oxime ( 9b ) (&#916;OD = 0). 7- O -dodecylnaringenin oxime ( 9b ) also inhibited the growth of S. aureus DSM799 (&#916;OD = 0.35) and C. albicans DSM1386 (&#916;OD = 0.22). The growth of A. alternata CBS1526 was inhibited as a result of the action of 7,4'-di- O -methylnaringenin ( 2a ), 7- O -ethylnaringenin ( 4a ), 7,4'-di- O -ethylnaringenin ( 5a ), 5,7,4'-tri- O -ethylnaringenin ( 6a ), 7,4'-di- O -pentylnaringenin ( 8a ), and 7- O -dodecylnaringenin ( 9a ) (&#916;OD in the range of 0.49-0.42) in comparison to that of the control culture (&#916;OD = 1.87). In the case of F. linii KB-F1, naringenin ( NG ), 7,4'-di- O -dodecylnaringenin ( 10a ), 7- O -dodecylnaringenin oxime ( 9b ), and 7,4'-di- O -dodecylnaringenin oxime ( 10b ) showed the strongest effect (&#916;OD = 0). 7,4'-Di- O -pentylnaringenin ( 8a ) and naringenin oxime ( NG-OX ) hindered the growth of A. niger DSM1957 (&#916;OD = 0)., Competing Interests: The authors declare no conflict of interest.

Thioflavanones are prevalent heterocyclic structural units in pharmaceutical and biologically active compound (Scheme ). In this paper, the synthesis of 2-phenylthiochroman-4-ones and 2-phenyl-4H-1-benzothiopyran-4-one labeled with carboxyl-14 is demonstrated., (Copyright © 2017 John Wiley & Sons, Ltd.)

To explore the structure-activity relationships of flavanonols on the inhibition of nitric oxide (NO) production in RAW 264.7 cells, we have prepared a series of synthetic flavanonols. In our previous study, the 2',3'-dihydroxyphenyl substructure was found to be the most potent B ring substructure among the flavanonols having 3,5,7-trihydroxychroman-4-one as the A/C ring. In this study, we examined the effect of diverse substitutions on the A ring of the 2-(2,3-dihydroxyphenyl)-3-hydroxychroman-4-one scaffold, i.e., by fixing the B ring to the 2',3'-dihydroxyphenyl substructure. Eighteen stereoisomers and 4 racemic mixtures were prepared, and their inhibitory potency on NO production in RAW 264.7 cells was tested. We observed higher inhibitory activity in the (2R,3R) stereoisomers than in the (2S,3S) stereoisomers. The presence of a hydroxy or a methoxy group at the 7-postiion enhanced the inhibitory potency, and the additional substitutions at the 6- or 8-position in the A ring increased potency and stereospecificity. A representative compound, (2R,3R)-2',3',7,8-tetrahydroxyflavanonol 5e, had an IC 50 value of 17µM, whereas its (2S,3S) stereoisomer did not inhibit NO production at all at a concentration of 100µM. In this study, it was necessary to determine the absolute configuration of the stereoisomers of the synthesized flavanonols that carry methoxy substitutions in the A ring. The procedure to determine their absolute configuration by the CD excitation chirality method is also discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Wogonin and astringin were synthesized from inexpensive chrysin and piceid in short steps. The key feature of these syntheses is site-selective transformation. The target molecules were obtained in 27 and 62% yields from the starting materials, respectively.

Gliomas are one of the most aggressive and treatment-resistant types of human brain cancer. Identification and evaluation of anticancer properties of compounds found in plants, such as naringenin (N) and 8-prenylnaringenin (8PN), are among the most promising applications in glioma therapy. The prenyl group seems to be crucial to the anticancer activity of flavones, since it may lead to enhanced cell membrane targeting and thus increased intracellular activity. It should be noted that 8PN content in hop cones is 10 to 100 times lower compared to other flavonoids, such as xanthohumol. In the study presented, we used a simple method for the synthesis of 8PN from isoxanthohumol- O -demethylation, with a high yield of 97%. Cellular accumulation and cytotoxicity of naringenin and 8-prenylnaringenin in normal (BJ) and cancer cells (U-118 MG) was also examined. Obtained data indicated that 8-prenylnaringenin exhibited higher cytotoxicity against used cell lines than naringenin, and the effect of both flavones was stronger in U-118 MG cells than in normal fibroblasts. The anticancer properties of 8PN correlated with its significantly greater (37%) accumulation in glioblastoma cells than in normal fibroblasts. Additionally, naringenin demonstrated higher selectivity for glioblastoma cells, as it was over six times more toxic for cancer than normal cells. Our results provide evidence that examined prenylated and non-prenylated flavanones have different biological activities against normal and cancer cell lines, and this property may be useful in designing new anticancer drugs for glioblastoma therapy., Competing Interests: No conflict of interest declared.

Background: Most of the available antimicrobial drugs have developed resistance, some of them suffer from severe toxicity and side effects. So, there is a need to discover novel compound(s) which should not only be potent, but also less toxic and cost effective., Objectives: The aim of the study is to develop new synthetic antimicrobial agents (Anti-bacterial and anti-fungal) such as 3-substituted flavone/flavanone derivatives, which should be significantly potent with low toxicity., Method: An attempt was made to synthesize a newer series of 3-methyl flavanone derivatives together with the synthesis of a series of 3- hydroxyl flavone analogues. The structures of the test compounds were elucidated and established by UV, IR, 1H-NMR, 13C-NMR and mass spectrometry. The synthesized compounds were subjected for in vitro antimicrobial screening using cup plate methods, followed by the determination of zone of inhibitions., Result: Two series (each 10) of 3-methyl flavanone and 3-hydroxy flavone derivatives were synthesized. The structures of the test compounds were characterized and established by various spectroscopic methods. The synthesized compounds were screened for in vitro antibacterial and antifungal activity against different strains (3-Gram positive, 3-Gram negative and 2- fungal strains)., Conclusion: Some of the 3- hydroxyl flavones derivatives (1b, 3b, 4b, and 5b) and 3- methyl flavanone derivatives (3a, 1a, 2a and 4a) were found to elicit potent antimicrobial activity. The study revealed that 3-hydroxy flavone derivatives were found to be most active against Gram negative, while 3-methyl flavanone derivatives were active against Gram positive bacteria., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A series of 5,7-dihydroxyflavanone derivatives were efficiently synthesized. Their antimicrobial efficacy on Gram-negative, Gram-positive bacteria and yeast were evaluated. Among these compounds, most of the halogenated derivatives exhibited the best antimicrobial activity against Gram-positive bacteria, the yeast Saccharomyces cerevisiae, and the Gram-negative bacterium Vibrio cholerae. The cytotoxicities of these compounds were low as evaluated on HepG2 cells using a cell viability assay. This study suggests that halogenated flavanones might represent promising pharmacological candidates for further drug development., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of 7-prenyloxy-2, 3-dihydroflavanone derivatives were synthesized and screened for their antidepressant-like activity. Among them, it was observed that compounds 5j and 5k were found to be the most antidepressant-like activity. In addition, it was found that compounds 5j and 5k significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus, and cortex. Compounds 5j and 5k also significantly increased the contents of 5-HIAA in the hippocampus and cortex, shut down 5-HT metabolism compared with mice treated with stress vehicle. These results suggested that compounds 5j and 5k displayed potent antidepressant-like properties that were mediated via neurochemical systems., (© 2015 John Wiley & Sons A/S.)

The emergence of albumin as a biocatalyst has created continuous interest of researchers for its application not only in the field of asymmetric oxidations and reductions but also in chemical reactions such as additions, condensations and eliminations. In the present work we report the cyclization reactions in presence of an albumin protein, Bovine Serum Albumin (BSA). The work is focused on cyclization of 2'-hydroxychalcone and 2'-aminochalcone to flavanones and azaflavanone, respectively. The results are supported by (1)H NMR studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The physicochemical properties and antioxidant activity of a molecule could be improved by the substitution of an oxygen atom in a molecule with selenium. We synthesized selenoflavanones and flavanones to evaluate their neuroprotective effects. The selenoflavanones showed improved physicochemical properties, suggestive of the ability to pass through the blood-brain barrier (BBB). They showed in vitro antioxidant effects against hydrogen peroxide, and did not result in severe cytotoxicity. Moreover, infarction volumes in a transient ischemia mouse model were significantly reduced by the selenoflavanone treatments.

Objective: To prepare baicalein liposome-lyophilized powder, and to investigate the particle size distribution, encapsulation efficiency, stability, in vitro release and in vivo pharmacokirietics in rats. METHODs: Baicalein liposome was prepared by the ethanol injection, the encapsulation efficiency was measured by column chromatography, glucose, lactose and mannitol were selected as lyoprotectants. Pharmacokinetics study in rats was carried out by oral administration and analysis of rats pharmacokinetic parameters., Results: The baicalein liposomes were spherical, the mean diameter was (93.1 ± 11.2) nm, PDI was 0.258, the encapsulation efficiency was (83.9 ± 0.4)%. In vitro release test results showed that it had a significant slow-release effect, freeze-dried mannitol for the best protective agent. The pharmacokinetic parameters of baicalein liposomes and solution were as follows: AUC(0 --> 24 (129.04 ± 12.73) μg/mL x h and (73.31 ± 9.34) μg/mL x h; C(max) (15.07 ± 3.13) μg/mL and (9.38 ± 2.42) μg/mL; T(max) 1 and 1.5 h., Conclusion: Baicalein liposome has the higher entrapment efficiency and the smaller particle size. In vitro studies show that baicalein liposome has a slow-release effect and can significantly improve the bioavailability in rats.

A class of flavanone was found to improve melanogenesis in B16F10 mouse melanoma cell line, but little is known about its target. Herein we described the synthesis and bioevaluation of sixteen 3',4',7-trihydroxyflavanone analogues and further synthesized a novel fluorescent flavanone-BODIPY, which could improve melanogenesis in B16F10 cell line by selectively binding to its endoplasmic reticulum. The fluorescent flavanone-BODIPY was proved to be a valuable probe for studying the localization of intracellular flavanone on living cells., (Copyright © 2015 Elsevier Ltd. All rights reserved.)