Structure-activity Relationships Of Flavonoids Research Articles

Inhibitory activities of flavonoids from Eupatorium adenophorum against acetylcholinesterase

Fifteen flavonoids isolated from the Eupatorium adenophorum showed inhibitory activities against acetylcholinesterase (AChE) isolated from Caenorhabditis elegans and Spodoptera litura. Their IC50 values ranged from 12.54 to 89.06μg/mL and 12.08 to 86.01μg/mL, respectively against the AChE isolated from the nematode and insect species. AChE was inhibited in a dose-dependent manner by all tested flavonoids, The isolated compound quercetagetin-7-O-(6-O-caffeoyl-β-D-glucopyranoside) displayed the highest inhibitory effect against AChE from C. elegans and S. litura, with IC50 values of 12.54 μg/mL and 12.58 μg/mL, respectively. The structure-activity relationship of flavonoids on the inhibitory activities indicated that additional phenolic hydroxyl groups in the glucose were favorable for their inhibitory effects and the degree of increase in inhibitory activity also depended on the number of phenolic hydroxyl groups. The Lineweaver-Burk and Dixon plots indicated that quercetagetin-7-O-(6-O-caffeoyl-β-d-glucopyranoside) is a reversible inhibitor against AChE. Quercetagetin-7-O-(6-O-caffeoyl-β-d-glucopyranoside), 5,4′-Dihydroxytlavone and quercetin-3-O-β-d-glucopyranoside inhibited AChE in a mixed-type competitive manner and these compounds might be the dual binding site AChE inhibitors. Further, nine compounds showed poisonous effects against C. elegans and inhibitory effects on the growth and development of S. litura.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs.

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Flavanoids derivatives from the root bark of Broussonetia papyrifera as a tyrosinase inhibitor

Materials developed from Broussonetia papyrifera have been widely used in food and paper industries, but this root bark of the plant has been overlooked despiteits potentially economic values. Thus, the aim of the present study was to develop the root bark of B. papyrifera as a source of bioactive compounds. Chemical investigation of the bark of B. papyrifera led to the isolation of nine flavonoids derivatives (1-9) and two coumarins (10-11), which includes five new compounds (1–4 and 11). The structures of isolates were elucidated based on spectroscopic analyses. All the isolates were evaluated for their biological effects including tyrosinase inhibition, cytotoxicity, and anti-inflammatory activity. Compound 3 showed inhibition activity against tyrosinase with an IC50 value of 9.29 μM (positive control, kojic acid: 30.56 μM). Molecular docking was used to support their inhibition activities which indicated that hydrogen bond formation played an important role in the ligand-enzyme complex. In addition, compound 4 exhibited cytotoxic activity against three cancer cell lines (NCI-H1975, HepG2, and MCF-7) and the structure-activity relationship of flavonoids (1-9) were established. Results from anti-inflammatory assay showed that compound 1 inhibited the production of IL-2 in Jurkat cells induced by phytohemagglutinin (PHA) and phorbol 12-myristate 13-acetate (PMA), with immunosuppressive activity. Overall, our study suggests that flavonoids from root bark of B. papyrifera can be used as a valuable source of bioactive compounds and support its use as a crop benefits to local economic.

The role of flavonoids in autoimmune diseases: Therapeutic updates.

Flavonoids are natural polyphenolic compounds which are included in a panoply of drugs and used to treat and/or manage human ailments such as metabolic, cardiovascular, neurological disorders and cancer. Thus, the purpose of this review is to emphasize the importance of flavonoids for the treatment of autoimmune diseases and put into the limelight of the scientific community several health-promoting effects of flavonoids which could be beneficial for the development of novel drugs from natural products. Despite available reviews on flavonoids targeting various disease conditions, a comprehensive review of flavonoids for autoimmune diseases is still lacking. To the best of our knowledge, this is the first attempt to review the potential of flavonoids for autoimmune diseases. The structure-activity relationship of flavonoids in this review revealed that the rearrangement and introduction of other functional groups into the basic skeleton of flavonoids might lead to the development of new drugs which will be helpful in relieving the painful symptoms of various autoimmune diseases.

Catechin, quercetin and taxifolin improve redox and biochemical imbalances in rotenone-induced hepatocellular dysfunction: Relevance for therapy in pesticide-induced liver toxicity?

Hepatotoxicity occurs as a result of adverse effects of some xenobiotics on the liver, which is often the target tissue of toxicity for environmental chemicals. Rotenone, used as a natural pesticide, is an environmental poison reported to cause organ toxicity. This study investigated the protective effect of three flavonoids, catechin, quercetin and taxifolin (2,3-Dihydroquercetin) in rotenone-induced hepatotoxicity. Male Wistar rats were administered rotenone for 10 days followed by post treatment with catechin (5, 10 and 20 mg/kg), quercetin (5, 10 and 20 mg/kg) or taxifolin (0.25, 0.5 and 1 mg/kg), respectively, for 3 days. Bioindices of oxidative stress and hepatocellular injury were measured in serum and tissue homogenate of animals. Rotenone intoxication produced liver damage in rats as reflected in alterations to activities/levels of enzymic and non-enzymic oxidative stress markers and enzymes linked with inflammation, as well as the transaminases, gamma glutamyl transpeptidase, bilirubin, and lactate dehydrogenase. Catechin, quercetin and taxifolin post treatment significantly attenuated these (p < 0.0001) rotenone-induced imbalances. Comparatively, quercetin displayed the best apparent ameliorative activity. It clearly showed superior activity to catechin. However, taxifolin appeared to show comparable activity to quercetin and better activity than catechin in some of the assays despite being administered at considerably lower doses. The results provide insight on the relative efficacy and structure-activity relationships of the selected flavonoids in ameliorating liver damage and also indicate that additional structural and metabolic factors may be involved in the structure-activity relationships of flavonoids.

Impact of specific functional groups in flavonoids on the modulation of platelet activation

Flavonoids exert innumerable beneficial effects on cardiovascular health including the reduction of platelet activation, and thereby, thrombosis. Hence, flavonoids are deemed to be a molecular template for the design of novel therapeutic agents for various diseases including thrombotic conditions. However, the structure-activity relationships of flavonoids with platelets is not fully understood. Therefore, this study aims to advance the current knowledge on structure-activity relationships of flavonoids through a systematic analysis of structurally-related flavones. Here, we investigated a panel of 16 synthetic flavones containing hydroxy or methoxy groups at C-7,8 positions on the A-ring, with a phenyl group or its bioisosteres as the B-ring, along with their thio analogues possessing a sulfur molecule at the 4th carbon position of the C-ring. The antiplatelet efficacies of these compounds were analysed using human isolated platelets upon activation with cross-linked collagen-related peptide by optical aggregometry. The results demonstrate that the hydroxyl groups in flavonoids are important for optimum platelet inhibitory activities. In addition, the 4-C=O and B ring phenyl groups are less critical for the antiplatelet activity of these flavonoids. This structure-activity relationship of flavonoids with the modulation of platelet function may guide the design, optimisation and development of flavonoid scaffolds as antiplatelet agents.

Structure-activity relationships of flavanones, flavanone glycosides, and flavones in anti-degranulation activity in rat basophilic leukemia RBL-2H3 cells.

The incidence of type I allergies, which are associated with mast cell degranulation and local inflammation, is increasing, and new treatments are needed. To date, structure-activity relationships of flavonoids in their degranulation-inhibiting activity have not been systematically characterized. In the current study, the degranulation-inhibiting activity of a series of flavonoids was evaluated. The following three observations were made: (1) the activity disappears when a sugar moiety is introduced into the A ring of the flavanone; (2) the activity depends on the number of hydroxyl groups on the B ring; (3) the activity is markedly enhanced when a double bond is introduced into the C ring. The information obtained in the current study may guide the development of a therapy for type I allergies.

Structure-activity relationships of flavonoids as natural inhibitors against E. coli β-glucuronidase

Bacterial β-glucuronidases play key roles in the deconjugation of a variety of endogenous and drug glucuronides, thus have been recognized as important targets to modulate the enterohepatic circulation of various glucuronides. In this study, more than 30 natural flavonoids were collected and their inhibitory effects against E. coli β-glucuronidase (EcGUS) were assayed. The results demonstrated that some flavonoids including scutellarein, luteolin, baicalein, quercetin and scutellarin displayed strong to moderate inhibitory effects against EcGUS, with the IC50 values ranging from 5.76 μM to 29.64 μM, while isoflavones and dihydroflavones displayed weak inhibitory effects against EcGUS. Further investigation on inhibition kinetics revealed that scutellarein and luteolin functioned as potent competitive inhibitors against EcGUS-mediated PNPG hydrolysis, with the Ki values less than 3.0 μM. Molecular docking simulations demonstrated that scutellarein and luteolin could be well-docked into the catalytic site of EcGUS, while the binding areas of these two natural inhibitors on EcGUS were highly overlapped with that of PNPG on EcGUS. Additionally, the structure-inhibition relationships of natural flavonoids against EcGUS are also summarized, which will be very helpful for the medicinal chemists to design and develop more potent flavonoid-type inhibitors against EcGUS.

Structure related effects of flavonoid aglycones on cell cycle progression of HepG2 cells: Metabolic activation of fisetin and quercetin by catechol-O-methyltransferase (COMT).

Dietary flavonoids are abundant in the Plant Kingdom and they are extensively studied because of their manifold pharmacological activities. Recent studies highlighted that cell cycle arrest plays a key role in their antiproliferative effect in different tumor cells. However, structure-activity relationship of flavonoids is poorly characterized. In our study the influence of 18 flavonoid aglycones (as well as two metabolites) on cell cycle distribution was investigated. Since flavonoids are extensively metabolized by liver cells, HepG2 tumor cell line was applied, considering the potential metabolic activation/inactivation of flavonoids. Our major observations are the followings: (1) Among the tested compounds diosmetin, fisetin, apigenin, lutelin, and quercetin provoked spectacular extent of G2/M phase cell cycle arrest. (2) Inhibition of catechol-O-methyltransferase enzyme by entacapone decreased the antiproliferative effects of fisetin and quercetin. (3) Geraldol and isorhamnetin (3'-O-methylated metabolites of fisetin and quercetin, respectively) demonstrated significantly higher antiproliferative effect on HepG2 cells compared to the parent compounds. Based on these results, O-methylated flavonoid metabolites or their chemically modified derivatives may be suitable candidates of tumor therapy in the future.

Rapid screening of transferrin-binders in the flowers of Bauhinia blakeana Dunn by on-line high-performance liquid chromatography–diode-array detector–electrospray ionization–ion-trap–time-of-flight–mass spectrometry–transferrin–fluorescence detection system

Transferrin (Transferrin, TRF, TF) has drawn increasing attention in cancer therapy due to its potential applications in drug delivery. TF receptor, highly expressed in tumor cells, recognizes and transports Fe3+-TF into cells to release iron into cytoplasm. Thus, discovering TF-binding compounds has become an active research area and is of great importance for target therapy. In this study, an on-line analysis method was established for screening TF-binding compounds from the flowers of Bauhinia blakeana Dunn using a high-performance liquid chromatography–diode-array detector–multi-stage mass spectrometry–transferrin–fluorescence detector (HPLC–DAD–MSn–TF–FLD) method. As a result, 33 of 80 identified or tentatively characterized compounds in the sample were TF-binding active. Twenty-five flavonol glycosides and eight phenolic acids were identified as TF-binders. Twelve of these active compounds together with six standard compounds were used to study the dose-response effects and structure-activity relationships of flavonoids and phenolic acids. The method was validated by vitexin with a good linearity in the range of concentrations used in the study. The limit of detection for vitexin was 0.1596 nmol. Our study indicated that the established method is simple, rapid and sensitive for screening TF-binding active compounds in the extract of Bauhinia blakeana Dunn, and therefore is important for discovering potential anti-cancer ingredients from complex samples for TF related drug delivery.

GW26-e5356 Structure-activity Relationships of Flavonoids in Plants of Ampelopsis Grossedentat on Inhibiting hKv1.5 Channels

GW26-e5356 Structure-activity Relationships of Flavonoids in Plants of Ampelopsis Grossedentat on Inhibiting hKv1.5 Channels

Soluble epoxide hydrolase inhibitory and anti-inflammatory components from the leaves of Eucommia ulmoides Oliver (duzhong).

Eucommia ulmoides leaves have been used as a functional food and drink in China. The purpose of this study was to identify the bioactive constituents with soluble epoxide hydrolase (sEH) inhibitory activity and anti-inflammatory properties. Twenty-seven known compounds (1-27) were isolated from the leaves of E. ulmoides Oliver, and their structures were identified by NMR and ESIMS analysis; three of these, 2,5-dimethoxy-3-glucopyranosyl cinnamic alcohol (11), foliasalacioside E2 (26), and icariside F2 (27), were obtained from this plant for the first time. Compounds 1-7 exhibited soluble epoxide hydrolase (sEH) inhibitory activity at 100 μM; among them, quercetin (1) and kaempferol (5) displayed potential activities with IC50 values of 22.5 ± 0.9 and 31.3 ± 2.6 μM, respectively, with noncompetitive inhibition mode. Nuclear factor kappa B (NF-κB) inhibitory activity of the isolated compounds was evaluated by the NF-κB liciferase assay in HepG2 cells. Compounds 1, 9, 20, and 27 displayed potent NF-κB inhibitory effects, with IC50 values of 15.14 ± 2.29, 15.23 ± 2.34, 16.88 ± 2.17, and 16.25 ± 2.19 μM, respectively, whereas other compounds showed weak inhibition of NF-κB transcriptional activity ranging from 17.54 to 92.6 μM. A structure-activity relationship of flavonoids 1-9 was also discussed. The results obtained in this work might contribute to the understanding of pharmacological activities of E. ulmoides leaves and further investigation on its potential application values for food and drug.

Structure Activity Relationships of Flavonoids as Potent α-Amylase Inhibitors

The effects of three flavonoids (quercetin, luteolin, diosmetin) on alpha-amylase were examined by enzymatic kinetics and fluorescence spectroscopy. The three test flavonoids were non-competitive inhibitors of the enzyme. Addition of flavonoids led to fluorescence quenching of alpha-amylase. The quenching was initiated from the formation of a complex between the flavonoids and the enzyme, corresponding to a static quenching process. An alpha-amylase molecule provides a binding site for the test flavonoid. The main binding force was hydrophobic. The decreasing order of inhibition of alpha-amylase by flavonoids and the binding force was luteolin, diosmetin, and quercetin. It is demonstrated that hydroxylation in ring C and methylation of the hydroxyl group in ring B of flavonoids may weaken the binding affinities to alpha-amylase.

Study on structure-activity relationship of flavonoids’ multidrug resistance-associated protein inhibitory activity

To study the quantitative structure-activity relationship (QSAR) between the stuctures of 29 flavonoids and the inhibitory activity of their multidrug resistance-associated protein (MRP) 1 and 2 by using the comparative molecular similarity index analysis (CoMSIA). By studying the impact of the combination of different molecular force fields, researchers obtained the molecular force fields that played an important role in inhibiting the activity of MRP1 and MRP2, built the optimized QSAR model, and discussed the structural modification method for flavonoids' multidrug resistance-associated protein inhibitor. The results of the study could not only provide the guidance for new drug R&D, but also help partially discuss the synergy mechanism between MRP1 and MRP2 receptors and traditional Chinese medicines containing flavonoids.

A Series of Natural Flavonoids as Thrombin Inhibitors: Structure-activity relationships

A series of natural flavonoids has been evaluated as potential inhibitors of thrombin using the optimized method of thrombin time. Myricetin and quercetin have shown to be the best thrombin inhibitors tested. In order to investigate the thrombin recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments. Structure-activity relationships of flavonoids (SARs) on thrombin would facilitate the design of chemical compounds with higher potency to serve as potential thrombin inhibitors, and provide information for the exploitation and utilization of flavonoids as thrombin inhibitors for thrombotic disease treatment.

Flavonoids: Recent Advances as Anticancer Drugs

Flavonoids belong to polyphenolic secondary metabolites with broad-spectrum pharmacological activities and extensive biological effects, and the most prominent activity is their potential role as anticancer agents. In recent years, flavonoids and their synthetic analogues have been intensely investigated in the treatment of ovarian, breast, cervical, pancreatic, and prostate cancer. To some extent, chemical structures of flavonoids will influence their anticancer activities. Thus, some new analogues based on the structural skeleton of these flavonoids have been synthesized and investigated. This review presents recent advances on the aspects of the natural flavonoids and their synthetic analogues in the treatment of cancers, and new synthetic approaches and possible structure-activity relationships of flavonoids are also briefly summarized.

Flavonols attenuate the immediate and late-phase asthmatic responses to aerosolized-ovalbumin exposure in the conscious guinea pig

We previously reported that quercetin and rutin have potent, anti-asthmatic activity, but the structure-activity relationships of flavonoids and anti-asthmatic agents are still poorly understood. In the current study, the effects of kaempferol, fisetin, and morin on the immediate-phase response (IAR) and late-phase response (LAR) caused by exposure to aerosolized-ovalbumin (OA) in OA-sensitized guinea pigs were evaluated by determining the specific airway resistance (sRaw), recruitment of leukocytes and chemical mediators in bronchoalveolar lavage fluid (BALF), histopathological surveys, and determination of neutrophil chemotaxis. Fisetin and kaempherol (30 mg/kg, p.o.) significantly ( P < 0.01) inhibited sRaw by 47.93% and 30.05% in IAR, and 54.45% and 40.50% in LAR, when compared to vehicle control, respectively. Furthermore, all three studied flavonols (30 mg/kg, p.o.) significantly ( P < 0.05) inhibited the recruitment of total, as well as subtypes of, leukocytes into the lung BALF. This recruitment inhibition corresponded to the inhibition of leukocyte infiltration, particularly of eosinophils and neutrophils, into the lung in pathological surveys and formly-methionyl-leucyl-phenylalanine (FMLP)-induced neutrophil chemotaxis studies. Kaempferol inhibited FMLP-induced neutrophil chemotaxis in a concentration-dependent manner in a tested range of 1–100 μM. Fisetin inhibited histamine content and peroxidase (EPO) activity in BALF in a dose-dependent manner. All three tested flavonols significantly ( P < 0.01) inhibited histamine content at 10 mg/kg, and phospholipase A 2 (PLA 2) and EPO activities at 30 mg/kg (p.o.) in BALF. Kaempherol had a greater anti-asthmatic effect than other flavonols. Fisetin demonstrated the greatest inhibition of sRaw, whereas morin had lesser effects. These results indicate that the lower the molecular weight, the greater the anti-asthmatic activities of these compounds.

Three-Dimensional Quantitative Structure-Activity Relationships of flavonoids and estrogen receptors based on docking

Flavonoids are endocrine disrupting compounds that occur ubiquitously in foods of plant origin. The Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR) model based on ligand-receptor docking is established between 20 flavonoids and estrogen receptor alpha (ERα), which may provide further theoretical basis for research on the relationship between flavones and estrogen. Comparative molecular field analysis (CoMFA) was employed and the best results of cross-validation and non cross validation were 0.845 and 0.988, respectively. Correspondingly, molecular similarity index analysis (CoMSIA) was employed and the results of cross-validation and non cross validation were 0.670 and 0.990, respectively. The CoMFA/CoMSIA and docking results reveal the structural features for estrogen activity and key amino acid residues in binding pocket, and provide an insight into the interaction between the ligands and these amino acid residues.

Structure−Activity Relationships of Flavonoids in the Cellular Antioxidant Activity Assay

Chemical antioxidant activity assays are used extensively to evaluate the potential bioactivity of plant foods and their phytochemical constituents, but they do not mimic the complexity of biological systems. The cellular antioxidant activity (CAA) activity assay was developed to be a more biologically relevant model to measure antioxidant activity. Structure-activity relationships of flavonoids have been determined in many chemistry antioxidant activity assays, and they vary with the protocols. The objective of this study was to determine structure-activity relationships of selected flavonoids in the CAA assay. The structures that conferred flavonoids with the most antioxidant activity in the CAA assay were a 3',4'- o-dihydroxyl group in the B-ring, a 2,3-double bond combined with a 4-keto group in the C-ring, and a 3-hydroxyl group. Isoflavones had no cellular antioxidant activity. Flavanols with a galloyl moiety had higher antioxidant activity than those without, and a B-ring 3',4',5'-trihydroxyl group further improved their efficacy. ORAC values for flavonoids were not related to their CAA values. Knowledge of structure-activity relationships in the CAA assay may be helpful in assessing potential in vivo antioxidant activity of flavonoids.

Theoretical evaluation of flavonoids as multipotent agents to combat Alzheimer's disease

As multiple pathogenetic factors, including aggregated amyloid-β peptide and tau protein, excessive transition metals, oxidative stress and reduced acetylcholine level, have been implicated in Alzheimer's disease (AD), multipotent agents aiming at diverse targets are expected to act better than the single-target-aiming counterparts in the fight against AD. Among the potential multipotent agents, natural products, especially flavonoids (including xanthones), have been given much attention. To explore to what extent the desired multiple pharmacological effects can be combined into one flavonoid molecule, we examined the structural requirements of flavonoids (including xanthones) as inhibitors of monoamine oxidase (including isoenzymes A and B), acetylcholinesterase and/or butyrylcholinesterase. In combination with the known structure-activity relationships of flavonoids as reactive oxygen species scavengers and metal chelators, we provide a theoretical evaluation of flavonoids (including xanthones) as multipotent agents to combat AD, which is of great significance to directing the screening of novel AD-modifying drugs.