ABSTRACT
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.
Subject(s)
Chalcones , Chromatography, High Pressure Liquid , Chalcones/chemistry , Chalcones/chemical synthesis , Spectrophotometry, Ultraviolet , Molecular Structure , Hydrogen-Ion Concentration , Flavanones/chemistry , Flavanones/chemical synthesis , Flavanones/analysis , Stereoisomerism , Solvents/chemistryABSTRACT
Aß1-42 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 (IC50 = 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 Aß1-42 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 AlCl3-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.
Subject(s)
Acetylcholinesterase , Alzheimer Disease , Amyloid beta-Peptides , Cholinesterase Inhibitors , Drug Design , Zebrafish , Alzheimer Disease/drug therapy , Animals , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Structure-Activity Relationship , Acetylcholinesterase/metabolism , Humans , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/pharmacology , Donepezil/pharmacology , Donepezil/chemical synthesis , Donepezil/chemistry , Blood-Brain Barrier/metabolism , Molecular Structure , Flavanones/pharmacology , Flavanones/chemical synthesis , Flavanones/chemistry , Dose-Response Relationship, Drug , Behavior, Animal/drug effectsABSTRACT
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 2.3eq and 1.2eq, respectively. Compounds 5f and 7k were reversible and excellent huAChE inhibitors with IC50 values of 0.91 µM and 0.57 µM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced Aß1-42 aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited huAChE-Aß1-40 aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu2+-induced Aß1-42 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.
Subject(s)
Alzheimer Disease/drug therapy , Amines/pharmacology , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Flavanones/pharmacology , Neuroprotective Agents/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amines/chemical synthesis , Amines/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Butyrylcholinesterase/metabolism , Cell Line , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Development , Flavanones/chemical synthesis , Flavanones/chemistry , Humans , Mice , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Protein Aggregates/drug effects , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antitussive Agents , Expectorants , Flavanones/pharmacology , Animals , Antitussive Agents/chemical synthesis , Antitussive Agents/chemistry , Antitussive Agents/pharmacology , Antitussive Agents/therapeutic use , Biological Availability , Cough/drug therapy , Cough/pathology , Disease Models, Animal , Drug Delivery Systems , Drug Evaluation, Preclinical , Drug Liberation , Expectorants/chemical synthesis , Expectorants/chemistry , Expectorants/pharmacology , Expectorants/therapeutic use , Flavanones/chemical synthesis , Flavanones/chemistry , Flavanones/therapeutic use , Mice , Nanoparticles , Particle Size , Solubility , SuspensionsABSTRACT
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 (IC50 = 9.7 µM) inhibitor. In addition, compound 3c significantly inhibited self-induced Aß1-42 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 Cu2+-mediated Aß1-42 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.
Subject(s)
Alzheimer Disease/drug therapy , Antioxidants/pharmacology , Carbamates/pharmacology , Cholinesterase Inhibitors/pharmacology , Flavanones/pharmacology , Neuroprotective Agents/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Butyrylcholinesterase/metabolism , Carbamates/chemical synthesis , Carbamates/chemistry , Cell Line , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Copper/pharmacology , Dose-Response Relationship, Drug , Drug Development , Flavanones/chemical synthesis , Flavanones/chemistry , Humans , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Protein Aggregates/drug effects , Rats , Structure-Activity RelationshipABSTRACT
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 inâ 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).
Subject(s)
Antineoplastic Agents/pharmacology , Arachidonate 12-Lipoxygenase/metabolism , Enzyme Inhibitors/pharmacology , Flavanones/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Flavanones/chemical synthesis , Flavanones/chemistry , Humans , Mice , Molecular Structure , Nitric Oxide/metabolism , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Aging/drug effects , Antioxidants/pharmacology , Caenorhabditis elegans Proteins/genetics , Flavanones/pharmacology , Forkhead Transcription Factors/genetics , Aging/genetics , Amino Acids/chemistry , Animals , Animals, Genetically Modified , Antioxidants/chemical synthesis , Antioxidants/chemistry , Caenorhabditis elegans/drug effects , Flavanones/chemical synthesis , Flavanones/chemistry , Longevity/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolismABSTRACT
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 (IC50, 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 IC50 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 (·O2-). In addition, compound 1 displayed good metal chelating properties and had anti-Aß aggregation activities. Therefore, compound 1 might be the potential anti-AD agent for further developments.
Subject(s)
Carbamates/pharmacology , Chelating Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Flavanones/pharmacology , Free Radical Scavengers/pharmacology , Acetylcholinesterase/chemistry , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Carbamates/chemical synthesis , Carbamates/metabolism , Chelating Agents/chemical synthesis , Chelating Agents/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Drug Design , Electrophorus , Flavanones/chemical synthesis , Flavanones/metabolism , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/metabolism , Horses , Kinetics , Molecular Docking Simulation , Molecular Structure , Peptide Fragments/metabolism , Protein Binding , Protein Multimerization/drug effects , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Bone Morphogenetic Protein 2/metabolism , Bone and Bones/metabolism , Flavanones/chemical synthesis , Flavanones/pharmacology , Fractures, Bone/drug therapy , Animals , Bone Morphogenetic Protein 2/genetics , Bone and Bones/drug effects , Cell Differentiation/drug effects , Gene Expression Regulation/drug effects , Humans , Molecular Structure , Osteoblasts/drug effects , Osteoporosis , Rats , Structure-Activity Relationship , Up-Regulation/drug effectsABSTRACT
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 (IC50 = 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.
Subject(s)
Antineoplastic Agents/chemical synthesis , CDC2 Protein Kinase/antagonists & inhibitors , Flavanones/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Cyclin B/metabolism , Drug Screening Assays, Antitumor , Flavanones/pharmacology , Flavonoids/pharmacology , Flavonoids/standards , Humans , MCF-7 Cells , Molecular Docking Simulation , Piperidines/pharmacology , Piperidines/standards , Protein Binding , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carcinoma, Renal Cell/metabolism , DNA Methylation/drug effects , Demethylation/drug effects , Flavanones/chemical synthesis , Kidney Neoplasms/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Chick Embryo , DNA Methylation/physiology , Dose-Response Relationship, Drug , Flavanones/pharmacology , HumansABSTRACT
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 (Cmax 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.
Subject(s)
Brain Neoplasms , Drug Delivery Systems/methods , Flavanones/administration & dosage , Glioblastoma , Nanoparticles/administration & dosage , Paclitaxel/administration & dosage , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Cell Line, Tumor , Drug Carriers/administration & dosage , Drug Carriers/chemical synthesis , Drug Liberation/drug effects , Drug Liberation/physiology , Estrogen Antagonists/administration & dosage , Estrogen Antagonists/chemical synthesis , Estrogen Antagonists/metabolism , Female , Flavanones/chemical synthesis , Flavanones/metabolism , Glioblastoma/drug therapy , Glioblastoma/metabolism , Lipids , Male , Nanoparticles/chemistry , Paclitaxel/chemical synthesis , Paclitaxel/metabolism , Particle Size , Peptides, Cyclic/administration & dosage , Peptides, Cyclic/chemical synthesis , Rats , Rats, WistarABSTRACT
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.
Subject(s)
Esters/pharmacology , Flavanones/pharmacology , Linolenic Acids/pharmacology , Receptors, G-Protein-Coupled/metabolism , Wound Healing/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Esters/chemical synthesis , Esters/chemistry , Flavanones/chemical synthesis , Flavanones/chemistry , Humans , Linolenic Acids/chemical synthesis , Linolenic Acids/chemistry , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Flavanones/pharmacology , Resveratrol/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Flavanones/chemical synthesis , Flavanones/chemistry , Humans , Resveratrol/chemical synthesis , Resveratrol/chemistry , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Flavanones/pharmacology , NF-kappa B/antagonists & inhibitors , Toll-Like Receptor 4/antagonists & inhibitors , Wilms Tumor/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Child , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Flavanones/chemical synthesis , Flavanones/chemistry , Humans , Mice , Mice, Nude , Molecular Structure , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Signal Transduction/drug effects , Structure-Activity Relationship , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Tumor Cells, Cultured , Wilms Tumor/metabolism , Wilms Tumor/pathologyABSTRACT
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 Cu2+-amyloid-ß (Aß)1-42 mediated cytotoxicity on PC12 cells. The thioflavine T (ThT) assay showed that 1 can effectively attenuate Cu2+-induced Aß1-42 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 Cu2+-Aß1-42-treated PC12 cells and elevate the superoxide dismutase (SOD) activity in Cu2+-Aß1-42-treated PC12 cells. The results show that N,N'-1,10-bis(naringin) triethylenetetraamine is a potential agent for therapy of Alzheimer's disease.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Antioxidants/pharmacology , Chelating Agents/pharmacology , Copper/metabolism , Flavanones/pharmacology , Peptide Fragments/metabolism , Trientine/pharmacology , Alzheimer Disease/drug therapy , Animals , Antioxidants/chemical synthesis , Antioxidants/therapeutic use , Cell Survival , Chelating Agents/chemical synthesis , Chelating Agents/therapeutic use , Flavanones/chemical synthesis , Flavanones/therapeutic use , Oxidative Stress/drug effects , PC12 Cells , Rats , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism , Trientine/chemical synthesis , Trientine/therapeutic useABSTRACT
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.
Subject(s)
Demethylation , Flavanones/chemical synthesis , Flavonoids/chemistry , Flavonoids/chemical synthesis , Microwaves , Propiophenones/chemistry , Research Design , Flavanones/chemistry , Lithium Chloride/chemistry , Temperature , Time FactorsABSTRACT
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.
Subject(s)
Flavanones/chemistry , Free Radical Scavengers/chemistry , Silicon Dioxide/chemistry , Antioxidants/chemistry , Flavanones/chemical synthesis , Free Radical Scavengers/chemical synthesis , Silicon Compounds/chemical synthesis , Spectroscopy, Fourier Transform Infrared , ThermogravimetryABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Flavanones/chemistry , Oximes/chemistry , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/isolation & purification , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Flavanones/chemical synthesis , Flavanones/pharmacology , Helicobacter pylori/drug effects , Helicobacter pylori/isolation & purification , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
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 (φF), 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.