Synthesis, Biological Evaluation, and SAR Studies of Varyingly Substituted 4-Thioflavonols

A series of 4-thioflavonols compounds were synthesized by treating flavonols with lawsons reagent with variable substituent groups at A, B, and AB rings. All the synthesized compounds were checked for antibacterial and antifungal activity. We report that many compounds were found active against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus, bacterial strains and, C. albicans, C. parapsilosisstrains and C. krusei fungal strains. Most of the synthesized 4-thioflavonols compounds were found to show enhanced antimicrobial activity than respective flavonol compounds.

Persimmon Leaf Flavonols Enhance the Anti-Cancer Effect of Heavy Ion Radiotherapy on Murine Xenograft Tumors

The cell cycle checkpoint system play a pivotal role in the cellular DNA damage response, and the discovery of checkpoint inhibitors is expected to sensitize current cancer therapies. Checkpoint signaling cascades are critically modulated by ATM (ataxia telangiectasia-mutated) and its related molecules. Generally, ATM primarily responds to ionizing irradiation-induced DNA double-strand breaks. Heavy ions from an accelerated carbon ion beam have been used to cure cancer because they are more effective than ionizing irradiation such as X-ray and γ-radiation in terms of biological damage. In a previous study, we demonstrated that a persimmon leaf flavonol (PLF) promoted the cytotoxic effect of chemotherapeutic agents on cancer cells through inhibition of checkpoint activities, especially in the ATM dependent pathway. The present study investigated whether PLF inhibits checkpoint activity during the DNA damage response induced by heavy ion irradiation. Treatment with PLF significantly increased the cytotoxicity of heavy ion irradiation in A549 adenocarcinoma cells. The phosphorylation of checkpoint proteins such as p53, SMC1, and Chk1 was increased by heavy ions. PLF reduced the phosphorylation of checkpoint proteins. Pre-treatment with PLF significantly prevented the decrease of mitotic cells in heavy ion-exposed cells. We further evaluated tumor volume in SCID mice inoculated with human lung adenocarcinoma A549 cells. The combination treatment of PLF and heavy ion resulted in a decrease of tumor volume compared with controls, although PLF itself did not exhibit any effect. These results indicate that PLF inhibits tumor growth through modulation of the DNA damage response. PLF may be useful for clinical application in combination with heavy ion radiotherapy.

Microwave Assisted-extraction of Flavonols from Acanthopanax Senticosus Harms and High-performance Liquid Chromatography Analysis

Flavonols were extracted from Acanthopanax Senticosus Harms by Soxhlet extraction（SE）,atmospheric pressure microwave-assisted extraction（AMAE） and pressurized microwave-assisted extraction（PMAE）.The influences of experimental conditions,such as concentration of ethanol in the eluent,microwave irradiation time,etc.on the extraction yield were studied.Four flavonols（hyperin,rutin,quercitrin and quercetin） in the extracts were determined quantitatively by HPLC method.The experimental results demonstrate the advantages of PMAE and AMAE over those of conventional SE,that is the extraction time is dramatically reduced,and the yields of flavonols are effective improved.Although the yield of flavonols is higher and the extraction time is shorter by PMAE than those of AMAE,flavonols are easy to be decomposed over a certain time.

Structure of Flavones and Flavonols. Part II: Role of Position on the O-H Bond Dissociation Enthalpy

The enthalpies of bond dissociations of the hydroxyl groups, the energy of the highest occupied molecular orbitals and the corresponding radicals spin densities of all possible ten isomeric mono-hydroxyl flavones are calculated by means of 3-parameter Becke, Lee, Yang and Parr functional. The structural factors affecting these descriptors of radical-scavenging activity are outlined. The results obtained show that the hydroxyl groups in ring A and C are more involved in the process of a radical-capturing than recently believed.

Molecular docking simulation analysis of the interaction of dietary flavonols with heat shock protein 90

Hsp90 is a major protein involved in the stabilization of various proteins in cancer cells.The present investigation focused on the molecular docking simulation studies of flavanols as inhibitors of Hsp90 at the high affinity adenosine triphosphate（ATP）binding site and analyzed absorption,distribution,metabolism,excretion and toxicity（ADME-toxicity）.The molecular docking analysis revealed that the flavanols showed competitive inhibition with ATP molecule at the active site and enhanced pharmacological parameters.

A concise total synthesis of natural flavonols

In this study,we designed a convenient method,to total synthesis of fl avonols especially for C-5 substituted ones and derivatives on a large scale.Beginning from the inexpensively available 2,4,6-trihydroxyacetophenone through Aldol condensation reaction,I2/DMSO cyclization reaction,Oxone“one pot”oxidation,kaempferol(1)and derivative(2)was obtained in an overall yield of 35%.The structures of the target compound and key intermediates were verifi ed by MS,IR,1H-NMR and 13C-NMR techniques,and the structure of 5a was further confi rmed by X-ray diff raction analysis.

Flavonols Induced by 5-Aminolevulinic Acid Are Involved in Regulation of Stomatal Opening in Apple Leaves

Flavonols, the main flavonoids in plant leaves, have newly been proposed as a H2O2 scavenger in guard cells. However, whether 5-aminolevulinic acid(5-ALA) is involved in regulating stomatal movement of apple(Malus × domestica Borkh. ‘Fuji') leaves through flavonol accumulation remains unclear. In this study, using diphenylboric acid 2-amino ethyl ester(DPBA, a flavonol fluorescent dye) and a laser scanning confocal microscope,we observed that 5-ALA pretreatment significantly improved flavonol accumulation in guard cells of apple leaves, especially around the nucleus.Then we demonstrated that 5-ALA pretreatment inhibited ABA-induced stomatal closure via decreasing reaction oxygen species(ROS) accumulation in guard cells. Pretreatment with quercetin or kaempferol, two main kinds of flavonols in plants, also inhibited ABA-induced stomatal closure by decreasing ROS content in the guard cells. Furthermore, exogenous flavonols could suppress H2O2-induced stomatal closure in apple leaves.Taken together, we conclude that ALA-induced flavonol accumulation in guard cells is involved in the inhibitory effect of ALA on ABA-induced ROS accumulation and stomatal closure in apple leaves.

An extraction-assay system： Evaluation on flavonols in plant resistance to Pb and Cd by supercritical extraction-gas chromatography

In this research, supercritical carbon dioxide extraction （SFE） showed better extraction etlect when compared with Solid- liquid extraction （SLE）, Soxhlet extraction （SEt and Ultrasonic extraction （UE）, not only in the rate but also the time. The comparison among these three extraction modifiers, including acetone, ethanol and methanol demonstrated that ethanol was preferred to SFE due to its high extraction effect and low toxicology. In addition, parameter of SFE, influence of temperature and pressure were investigated, and the best extraction effect was achieved at the optima conditions, temperature of 40℃ and the pressure of 35 MPa. Thus, SFE is a highly effective method for flavonols extraction, requiring minimum energy and producing non-toxic byproduct. SFE-GC system is applied for the evaluation on flavonols that plays a key role in plant resistance to heavy metal, with its content and synthetase gene expression significantly increasing in plant when threatened by heavy metal. Besides, results indicated that flavonols can improve plant resistance to oxidative stress by quenching the redundant ROS in matrix.

Diff erences in pigment circadian rhythmicity in greenand red-leafed tree species in the sun and shade

Light fl ux and quality are crucial factor for setting endogenous plant circadian rhythms.Evaluating the daily rhythmicity of leaf chlorophyll content is an eff ective method to monitor the plant physiological endogenous clock in response to environmental signals such as light availability/quality.Here,we used a leaf-clip sensor to monitor diurnal rhythms in the content of chlorophyll and fl avonoids such as fl avonols and anthocyanins in three green-(Ailanthus altissima,Tilia platyphyllos and Platanus×acerifolia)and two red-leafed(Acer platanoides cv.Crimson King and Prunus cerasifera var.pissardii)tree species,adapted to sun(L)or shade(S).Signifi cant diff erences in chlorophyll content(Chl)and its variations during the day were observed among treatments in all the analyzed species.S-plants had more Chl than L-plants irrespective of leaf color,and Chl variations were more distinct during the day than in L-plants.In particular,contents were lowest in the morning(9:00)and in the middle of the day(at 12:00 and 15:00),and the highest at dusk(21:00).The less evident trends in Chl variation in L-plants were attributed to a decrease in Chl content in high light,which likely masked any increases in the shaded counterparts during the afternoon.Daily fl avonol levels did not vary no notably during the day.In sun-exposed red leaves,anthocyanins partially screened mesophyll cells from incident light,and its levels were similar to the Chl dynamics in the shaded counterparts.This study provides new bases for further work on endogenous rhythms of plant pigments and improves our understanding of plant physiology in the context of day/night rhythmicity.

Polyphenolic Compounds and Antioxidant Activity of Sea Buckthorn(Hippophae rhamnoides L.)

The fruits of the Sea buckthorn(Hippophae rhamnoides L.)are a popular plant food and a valuable health product.Cultivating plants produces a lot of leaves with fine branches as an unnecessary residue,which needs valorization.The aim of the study was to estimate(by HPLC-MS/MS)the qualitative and quantitative content of polyphenolic compounds in different parts of H.rhamnoides(HR),and to determine the level of antioxidant activity of leaves and fruits(by DPPH,ABTS methods and ferrozine test).Up to 19 compounds were identified in different parts of HR.The fruits are rich in flavonoids,including various glycosides of flavonols isorhamnetin,quercetin,and kaempferol.Two isorhamnetin glycosides were not identified in the leaves,while isorhamnetin-3-rhamnosylglactosides and the ellagitannins hippophaenin B,stachyurin and casuarinin were present only in the leaves of the plant.The bark and roots contained considerably more catechins,but minimal flavonols than the fruits and leaves of HR.The total phenolics and flavonols were most abundant in water infusions from leaves of HR(especially quercetin-3-O-glucoside-7-O-rhamnoside),compared to methanolic extracts.No significant differences in the quantitative and qualitative content of the fresh and dried leaves were detected.The highest antioxidant activity by all three methods was detected in the leaves of HR.In addition to the fruits,the leaves may have a perspective as a source of biologically active substances of HR.

Quercetin-derivatives painting the yellow petals of American lotus(Nelumbo lutea)and enzymatic basis for their accumulation

American lotus(Nelumbo lutea)is one of the two species in Nelumbo and has only yellow flower.Identification of total flavonoids showed wild American lotus contained almost only flavonols with quercetin 3-O-glucuronide to be the dominant pigment.The variation tendency of the total flavonol content was coincident with yellow color variation of petals during flower development.To understand the mechanism of accumulation and constituent of pigments in petals,three pivotal genes,NlFLS1,NlFLS2 and NlFLS3,which were predicted to encode flavonol synthases were isolated and characterized by analyses of basic bioinformatics,temporal and spatial expression patterns and enzymatic activity.Their temporal expression levels showed the same variation tendency,which was also consistent with the development-dependent variation of total flavonol content.Spatial expression patterns indicated the three genes should function in petals.All the three proteins were demonstrated to be bifunctional dioxygenase,possessing both flavonol synthase activity and flavanone 3-hydroxylase activity.Besides,other flavonol biosynthesis related genes were also investigated on their expression levels to give more clues on the mechanism.Substrate preferences of the three FLSs,substrate competitions between the FLSs and other flavonol biosynthesis related enzymes,and the greatly differential expression levels between F3’H(flavonoid 3-hydroxylase)and F3’5’H(flavonoid 3,5-hydroxylase)contributed to the flavonol constituent in the petals of America lotus,namely abundant quercetin-derivatives while very few kaempferol-derivatives and myricetin-derivatives.

Review of anticancer mechanisms of isoquercitin

This review was based on a literature search of PubM ed and Scielo databases using the keywords "quercetin,rutin,isoquercitrin,isoquercitin(IQ),quercetin-3-glucoside,bioavailability,flavonols and favonoids,and cancer" and combinations of all the words.We collected relevant scientific publications from 1990 to 2015 about the absorption,bioavailability,chemoprevention activity,and treatment effects as well as the underlying anticancer mechanisms of isoquercitin.Flavonoids are a group of polyphenolic compounds widely distributed throughout the plant kingdom.The subclass of flavonols receives special attention owing to their health benefits.The main components of this class are quercetin,rutin,and IQ,which is a flavonoid and although mostly found as a glycoside,is an aglycone(lacks a glycoside side chain).This compound presents similar therapeutic profiles to quercetin but with superior bioavailability,resulting in increased efficacy compared to the aglycone form.IQ has therapeutic applications owing to its wide range of pharmacological effects including antioxidant,antiproliferative,anti-inflammatory,anti-hypertensive,and anti-diabetic.The protective effects of IQ in cancer may be due to actions on lipid peroxidation.In addition,the antitumor effect of IQ and its underlying mechanism are related to interactions with Wnt signaling pathway,mixed-lineage protein kinase 3,mitogen-activated protein kinase,apoptotic pathways,as well proinflammatory protein signaling.This review contributed to clarifying the mechanisms of absorption,metabolism,and actions of IQ and isoquercitrin in cancer.

Dietary flavonoid intake and risk of stomach and colorectal cancer

Stomach and colorectal cancers are common cancers and leading causes of cancer deaths.Because the alimentary tract can interact directly with dietary components,stomach and colorectal cancer may be closely related to dietary intake.We systematically searched published literature written in English via PubMed by searching for terms related to stomach and colorectal cancer risk and dietary flavonoids up to June 30,2012.Twenty-three studies out of 209 identified articles were finally selected for the analysis.Log point effect estimates and the corresponding standard errors were calculated using covariate-adjusted point effect estimates and 95%CIs from the selected studies.Total dietary flavonoid intake was not associated with a reduced risk of colorectal or stomach cancer [odds ratio(OR)(95%CI) = 1.00(0.90-1.11) and 1.07(0.70-1.61),respectively].Among flavonoid subclasses,the intake of flavonols,flavan-3-ols,anthocyanidins,and proanthocyanidins showed a significant inverse association with colorectal cancer risk [OR(95%CI) = 0.71(0.63-0.81),0.88(0.79-0.97),0.68(0.56-0.82),and 0.72(0.61-0.85),respectively].A significant association was found only between flavonols and stomach cancer risk based on a limited number of selected studies [OR(95%CI) = 0.68(0.46-0.99)].In the summary estimates from casecontrol studies,all flavonoid subclasses except flavones and flavanones were inversely associated with colorectal cancer risk,whereas neither total flavonoids nor any subclasses of flavonoids were associated with colorectal cancer risk in the summary estimates based on the cohort studies.The significant association between flavonoid subclasses and cancer risk might be closely related to bias derived from the case-control design.There was no clear evidence that dietary flavonoids are associated with reduced risk of stomach and colorectal cancer.

Synthesis, characterization, antibacterial and anticancer evaluation of some novel flavone-3-ols

A series of novel flavonols were synthesized by cyclizing corresponding hydoxy chalcones using Algar flynn Oyamada reaction (1)The synthesized compounds were characterized by various spectrochemical methods including IR, MASS, NMR spectroscopy. Out of 13 compounds screened for antibacterial activity [2], compound VMF 12 (a bromo derivative) showed activity with an IC50value at 0.16μM against S. aureus.

Indigenous Purple Vegetable Extracts Protect against Hydrogen Peroxide-Induced DNA Damage in Human Lymphocytes

The objectives of this study were to identify the antioxidants in acid hydrolysates of six of Taiwan’s indigenous purple-leaved vegetables (IPLV), including purple-leaved sweet potato (Ipomoea batatas L. Lamark), purple-leaved gynura line 1 (Gynura bicolor D.C.), purple-leaved gynura line 2 (Gynura bicolor D.C.), purple-leaved perilla line 1 (Perilla frutescents L. Britton), bicolored-leaved perilla line 2 (Perilla frutescens L. Britton), and heartleaf houttuynia (Houttuynia cordata Thumb.). Their antioxidant activity and ability to protect DNA from oxidative damage was also evaluated. The antioxidants identified included flavonoids, anthocyanidins and flavonols. Both purple-leaved perilla line 1 and bicolored-leaved perilla line 2 were found to be abundant in cynidin, malvidin, and myricetin. Moreover, purple-leaved sweet potato and heartleaf houttuynia were found to be abundant in quercetin. Purple-leaved sweet potato and purple-leaved perilla line 1 contained significantly higher inhibition percentages of conjugated diene formation than other vegetables. Purple-leaved sweet potato, heartleaf houttuynia, purple-leaved perilla line 1, and bicolored-leaved perilla line 2 had better inhibition percentages of tail DNA% and tail moment in the study. In conclusion, the abovementioned four indigenous purple-leaved vegetables abounded in antioxidants had strong antioxidant activity for protecting DNA in lymphocytes from oxidative damages.

Chemical characterization and antioxidative properties of Polish variety of Morus alba L. leaf aqueous extracts from the laboratory and pilot-scale processes

White mulberry tree (Morus alba L) is cultivated throughout Asia and Europe, including Poland. The leaves and root bark preparations from Morus alba have been used in traditional phytomedicine. The objective of the present study was to compare chemical composition and antioxidative activity of aqueous extracts prepared from Polish variety of Morus alba leaves at the laboratory (L) and pilot plant scale (PP) conditions. Proximate composition, phenolic acids profile (HPLC/MS), flavonol glicosides (HPLC/ MS), polyphenols (Folin-Ciocalteu assay), and the antioxidant activity (ABTS and DPPH assay) of the extracts were determined. The main phenolic compounds were identified as gallic, protocatechuic, phydroxybenzoic, vanillic, chlorogenic, caffeic, p-coumaric, ferulic, and sinapic acids. Chlorogenic acid was the main phenolic constituent of both extracts. The flavonols fraction contained rutin, quercetin 3-β-D-glucoside, and kaempferol 3-β-D- glucopyranoside. Total concentration of phenolic compounds were 7.9 g and 14.4 g gallic acid equivalent/100 g extract, and antioxidant activity was 137.1 and 214.1 μMol Trolox equivalent/g dry weight for the PP and L extracts, respectively. We concluded that current pilot plant process is less efficient than laboratory process at the aqueous extraction of bioactive components from Morus alba dried leaves. Potential improvements may include increasing efficacy of the extraction, decreasing losses of bioactive components during the process, or both.

Antidiabetic and in vitro antioxidant potential of Hybanthus enneaspermus(Linn) F.Muell in streptozotocin—induced diabetic rats

Objective:To evaluate antidiabetic and antioxidant potential of Hybanthus enneaspermus in different models.Methods:The oral glucose tolerance test(OGTT) and normoglycemic effect of alcoholic extract of Hybanthus enneaspermus(AHE) were evaluated at a dose of 125,250 and 500mg/kg p.o.while hypoglycemic activity and effect on body weight were tested at 250 and 500 mg/kg p.o.per day for 21 days in Streptozotocin(STZ) induced diabetic rats.Further,glucose uptake by hemidiaphram was also evaluated.The total polyphenolic and flavonoid were determined and their correlation with various antioxidant assays was also determined.Results:The results showed high level of phenolic content in AHE.AHE also exhibited higher total antioxidant capacity,good reducing power and a significant scavenger of reactive oxygen species like DPPH radical,nitric oxide,hydrogen peroxide and deoxyribose.Furthermore there was a significant increase in the body weight and decrease in the blood glucose level on treatment with the AHE.AHE increased glucose uptake on isolated rat hemi-diaphragm compared to control group.Conclusions:AHE reduce blood glucose level in STZ-induced diabetic model.It does not show significant effect in normoglycemic study but showes significant effect in OGT.AHE has significant antioxidant activity,which may be attributed to high phenolic content.

A New Isoprenylated flavonol from the Leaves of Broussonetia kazinoki

A new isoprenylated flavonol, named broussonol A (1) was isolated from the leaves of Broussonetia kazinoki Sieb. The structure of broussonol A was characterized by chemical and spectral methods.

A New Antimicrobial Flavonol Glycoside from Alchornea davidii

A new flavonol glycoside, isorhamnetin-3-O-b-D-xyloside, was isolated from the extract of leaves and twigs of Alchornea davidii (Euphorbiaceae). Its structure was established on the basis of the spectral analysis and chemical degradation. Antimicrobial assay showed that it moderately inhibited the growth of test bacteria (Staphylococcus aureus, Bacillus subtilis and Pseudomonas fluorescens) and fungi (Candida albicans, Aspergillus niger and Trichophyton rubrum) with MICs at 50 g/mL.

A Flavonol Glycoside from Smilax glabra

A new flavonol glycoside, named neosmitilbin was isolated form the rhizome of Smilax glabra. Its structure and absolute configuration were elucidated on the basis of spectroscopic studies.