- Design and synthesis of 7-O-1,2,3-triazole hesperetin derivatives to relieve inflammation of acute liver injury in mice
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Based on the previous research results of our research group, to further improve the anti-inflammatory activity of hesperetin, we substituted triazole at the 7-OH branch of hesperetin. We also evaluated the anti-inflammatory activity of 39 new hesperetin derivatives. All compounds showed inhibitory effects on nitric oxide (NO) and inflammatory factors in lipopolysaccharide-induced RAW264.7 cells. Compound d5 showed a strong inhibitory effect on NO (half maximal inhibitory concentration = 2.34 ± 0.7 μM) and tumor necrosis factor-α, interleukin (IL)-1β, and (IL-6). Structure–activity relationships indicate that 7-O-triazole is buried in a medium-sized hydrophobic cavity that binds to the receptor. Compound d5 can also reduce the reactive oxygen species production and significantly inhibit the expression of inducible NO synthase and cyclooxygenase-2 through the nuclear factor-κB signaling pathway. In vivo results indicate that d5 can reduce liver inflammation in mice with acute liver injury (ALI) induced by CCI4. In conclusion, d5 may be a candidate drug for treating inflammation associated with ALI.
- Zheng, Yan,Zhang, Yi-long,Li, Zeng,Shi, Wen,Ji, Ya-ru,Guo, Ya-Hui,Huang, Cheng,Sun, Guo-ping,Li, Jun
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- Enhanced antioxidant, anti-inflammatory and α-glucosidase inhibitory activities of citrus hesperidin by acid-catalyzed hydrolysis
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Hesperidin hydrolysates (HHS) was produced by the hydrolysis of hesperidin (HDN) in previous studies. The potential components in HHS were identified by LC-MS, and minor components (MCS) in HHS were isolated. Antioxidant activities by radical-scavenging capacities, reducing capacity and β-carotene-linoleate assay, anti-inflammatory effects by inhibiting NO production of RAW 264.7 cells, and α-glucosidase inhibitory effects of HDN, HHS, MCS and henperetin (HTN) were investigated in present study. HHS showed higher radical scavenging activities, higher reducing capacity, and higher inhibitory activity in the β-carotene-linoleate assay than HDN. HHS inhibited the production of NO and pro-inflammatory cytokines of RAW 264.7 cells more strongly than HDN. HHS also intensively inhibited α-glucosidase activity whereas HDN showed little activity. In addition, the effects of MCS on above activities showed it play a synergistic part with HTN. This work suggested that hydrolyzation of HDN enhance the activities, and provided valuable information on effective utilization of HDN.
- Lu, Shengmin,Xing, Jianrong,Zheng, Meiyu
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- Hesperetin as an inhibitor of the snake venom serine protease from Bothrops jararaca
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The majority (90%) of the snakebite envenomation in Brazil accounts for Bothrops from the Viperidae family. Some snake venom serine proteases provoke blood coagulation in ophidian accident victims because of their fibrinolytic activity, one of those proteases from Bothrops jararaca (B. jararaca) has been chosen for this study. Our objectives were to isolate and characterize the target serine protease; isolate, purify, and characterize the orange bagasse flavone (hesperetin, Hst), and investigate the interactions between the targets, enzyme, and hesperetin. The purified serine protease was named BjSP24 because of its molecular mass and proteolytic activity. BjSP24 was folded and characterized using circular dichroism and showed low alpha-helix contents (7.7%). BjSP24 exhibited sequence similarity to other known snake venom serine proteases as measured in the enzyme tryptic peptides' LC-MS/MS run. Hesperetin was obtained within the expected yield and with the predominance of 2S isomer (82%). It acted as a mixed inhibitor for the serine protease (SVSP) from Bothrops jararaca snake venom observed in three different in vitro experiments, fluorescence, kinetics, and SSTD-NMR. It is still to determine if hesperetin might aid-in reverting the on site blood clotting problems just after snakebite accidents.
- dos Santos, Roney Vander,Grillo, Giovanna,Fonseca, Henrique,Stanisic, Danijela,Tasic, Ljubica
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- Discovery of Novel Bacterial Chalcone Isomerases by a Sequence-Structure-Function-Evolution Strategy for Enzymatic Synthesis of (S)-Flavanones
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Chalcone isomerase (CHI) is a key enzyme in the biosynthesis of flavonoids in plants. The first bacterial CHI (CHIera) was identified from Eubacterium ramulus, but its distribution, evolutionary source, substrate scope, and stereoselectivity are still unclear. Here, we describe the identification of 66 novel bacterial CHIs from Genbank using a novel Sequence-Structure-Function-Evolution (SSFE) strategy. These novel bacterial CHIs show diversity in substrate specificity towards various hydroxylated and methoxylated chalcones. The mutagenesis of CHIera according to the substrate binding models of these novel bacterial CHIs resulted in several variants with greatly improved activity towards these chalcones. Furthermore, the preparative scale conversion catalyzed by bacterial CHIs has been performed for five chalcones and revealed (S)-selectivity with up to 96 % ee, which provides an alternative biocatalytic route for the synthesis of (S)-flavanones in high yields.
- Bornscheuer, Uwe T.,Brückner, Stephan I.,Gei?ler, Torsten,Gross, Egon,Hartmann, Beate,Ley, Jakob P.,Meinert, Hannes,R?ttger, Carsten,Schuiten, Eva,Yi, Dong,Zirpel, Bastian
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supporting information
p. 16874 - 16879
(2021/07/06)
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- Synthesis of 5-Hydroxy-3′,4′,7-trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2-Mediated Anticancer Drug Resistance
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3′,4′,7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3′,4′-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI50). Of the synthesized compounds, the reversal effect of 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF, RI50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI50 18 nm). Fluoro-substituted 5-fluoro-3′,4′,7-trimethoxyflavone (FTMF, RI50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3′,4′-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.
- Tsunekawa, Ryuji,Katayama, Kazuhiro,Hanaya, Kengo,Higashibayashi, Shuhei,Sugimoto, Yoshikazu,Sugai, Takeshi
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p. 210 - 220
(2018/10/15)
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- 7-O-amido substituted hesperidin derivative and preparation method and application thereof
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The invention discloses a 7-O-amido substituted hesperidin derivative and a preparation method and application thereof. The 7-O-amido substituted hesperidin derivative has the structural formula shownin a formula (I) (please see the specification for the formula (I)). Further pharmacological activity studies show that the related amido substituted hesperidin derivative can inhibit the release ofNO in a concentration dependency mode, production of inflammatory mediators of IL-6 and TNF-alpha is reduced, and compared with indomethacin and celecoxib, a compound 4d shows better inhibition of inflammatory activity, and significantly inhibits expression of nitric oxide synthase (iNOS) and COX-2; and the compound has the potential and value for development into anti-inflammatory drugs, and thecompound 4d is expected to be a candidate drug with the anti-inflammatory activity.
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Paragraph 0036-0041
(2019/11/12)
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- Design, synthesis and investigation of the potential anti-inflammatory activity of 7-O-amide hesperetin derivatives
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To develop new anti-inflammatory agents, a series of 7-O-amide hesperetin derivatives was designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. All compounds showed inhibitory effect on LPS-induced NO production. Among them, 7-O-(2-(Propylamino)-2-oxoethyl)hesperetin (4d) and 7-O-(2-(Cyclopentylamino)-2-oxoethyl)hesperetin (4k) with hydrophobic side chains exhibited the most potent NO inhibitory activity (IC50 = 19.32 and 16.63 μM, respectively), showing stronger inhibitory effect on the production of pro- inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) than indomethacin and celecoxib at 10 μM. The structure-activity relationships (SARs) suggested that the 7-O-amide unit was buried in a medium-sized hydrophobic cavity of the bound receptor. Furthermore, compound 4d could also significantly suppress the expression of inducible nitric oxide synthase enzymes (iNOS) and cyclooxygenase-2 (COX-2), through the nuclear factor-kappa B (NF-κB) signaling pathway.
- Zhang, Yilong,Zheng, Yan,Shi, Wen,Guo, Yahui,Xu, Tao,Li, Zeng,Huang, Cheng,Li, Jun
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- Design, synthesis and investigation of potential anti-inflammatory activity of O-alkyl and O-benzyl hesperetin derivatives
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Hesperetin has been known to exert several activities such as anti-oxidant, antitumor and anti-inflammatory. To find hesperetin derivatives showing better activity, sixteen novel hesperetin derivatives were designed and synthesized. The new obtained compo
- Huang, Ai-Ling,Zhang, Yi-Long,Ding, Hai-Wen,Li, Bo,Huang, Cheng,Meng, Xiao-Ming,Li, Jun
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- Functionalities tuned enantioselectivity of phenylcarbamate cyclodextrin clicked chiral stationary phases in HPLC
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The mixed chloro- and methyl- functionalities can greatly modulate the enantioselectivities of phenylcarbamate cyclodextrin (CD) clicked chiral stationary phases (CSPs). A comparison study is herein reported for per(4-chloro-3-methyl)phenylcarbamate and per(2-chloro-5-methyl)phenylcarbamate β-CD clicked CSPs (i.e., CCC4M3-CSP and CCC2M5-CSP). The enantioselectivity dependence on column temperature was studied in both normal-phase and reversed-phase mode high performance liquid chromatography (HPLC). The thermodynamic study revealed that the stronger intermolecular interactions can be formed between CCC4M3-CSP and chiral solutes to drive the chiral separation. The higher enantioselectivities of CCC4M3-CSP were further demonstrated with the enantioseparation of 17 model racemates in HPLC.
- Tang, Jian,Lin, Yuzhou,Yang, Bo,Zhou, Jie,Tang, Weihua
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p. 566 - 573
(2017/08/26)
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- Enhanced antioxidant activity, antibacterial activity and hypoglycemic effect of luteolin by complexation with manganese(II) and its inhibition kinetics on xanthine oxidase
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The present study aims to improve the biological activities of luteolin by complexation with manganese(ii). UV-visible spectroscopy, infrared spectroscopy, thermogravimetric analysis and elemental analysis were adopted to assess the relevant interaction of luteolin and manganese(ii) ions and the chelation sites. The antioxidant activity, hypoglycemic effect and antimicrobial activity of luteolin-manganese(ii) complex with respect to its parent luteolin and the inhibition effect of which on xanthine oxidase were investigated and compared. The spectroscopic data indicated that luteolin reacts with manganese(ii) cations through the chelation sites of 5-hydroxy and 4-carbonyl in two luteolin molecules. Antioxidant and antibacterial activity were enhanced after the complexation of manganese(ii) cations with luteolin. An inhibition effect assay found that luteolin and luteolin-manganese(ii) complex reversibly inhibited xanthine oxidase in a competitive manner. Luteolin-manganese(ii) complex had a more remarkable hypoglycemic effect than luteolin by increasing the glucose consumption in liver tissue.
- Dong, Hao,Yang, Xiaocui,He, Jiapeng,Cai, Sheng,Xiao, Kaijun,Zhu, Liang
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p. 53385 - 53395
(2017/12/02)
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- Hesperetin esterified compound and preparation method and application thereof
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The invention relates to a hesperetin esterified compound and a preparation method and an application thereof. The structural formula of the hesperetin esterified compound is as shown in the description, wherein R1 is H or C1-C4 alkyl; R2-R6 are respectively one of H, halogen, nitryl, alkyl and alkoxyl. According to the hesperetin esterified compound, by taking hesperetin as a mother core structure, a benzenesulfonic acid group is introduced through hydroxyl at site 7 of hesperetin, so that the characteristics of unique electronic characteristic and excellent bioactivity and the like of hesperetin are kept, the hesperetin has anti-tumor activity, and the hesperetin, benzenesulfonic acid and a derivative thereof are connected through covalent bonds to form twin drugs which are metabolized in vivo to generate hesperetin and benzenesulfonic acid as well as the derivative thereof. The two drugs have a synergistic effect, so that the antitumor activity of the hesperetin esterified compound is enhanced. Meanwhile, the selectivity of the antitumor activity is improved to a certain extent and adverse reactions of the drugs are reduced.
- -
-
Paragraph 0064; 0078; 0080
(2017/08/31)
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- Enzymatic deglycosylation of flavonoids in deep eutectic solvents-aqueous mixtures: Paving the way for sustainable flavonoid chemistry
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The low solubility of glycosylated flavonoids represents a hurdle to conduct efficient enzymatic deglycosylations in aqueous media. To overcome this drawback, environmentally-unfriendly dimethylsulfoxide (DMSO) is typically used as co-solvent. Using a specific diglycosidase from Acremonium sp. DSM24697 for the deglycosylation of the rutinosylated flavonoid (hesperidin) as model reaction, this communication explores the use of (non-hazardous and biodegradable) deep eutectic solvents (DESs) as co-solvents in flavonoid biocatalysis. The enzymatic deglycosylation was observed when DES composed of choline chloride and glycerol or ethylene-glycol was used at proportions of up to 40% (DES-Buffer, v/v), displaying a promising framework to combine enhanced flavonoid solubilities and high enzymatic activities. The deglycosylation activity significantly increased when the single DES components - glycerol and ethylene-glycol - were added (e.g. 140% of enzyme activity at glycerol at 40% v/v), whereas deleterious effects were observed when choline chloride was solely added, presumably due to its chaotropic effect. Future research opportunities may be envisaged in the genetic design to evolve more robust biocatalysts, and in tailoring DES to deliver more enzyme-compatible solvents.
- Weiz, Gisela,Braun, Lucas,Lopez, Rosana,De María, Pablo Domínguez,Breccia, Javier D.
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- Zhaoqing hesperetin hydrazone compound and application thereof
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The invention belongs to fields of development and utilization of local Chinese medicinal herbs resources, structural modification of extracts and pharmaceutical research, and relates to a Zhaoqing hesperetin hydrazone compound and its application. According to the Zhaoqing hesperetin hydrazone compound, Zhaoqing citrus peels are used as a raw material to extract hesperidin and prepare hesperetin, and by using hesperetin as a lead compound, a p-chlorophenylhydrazine condensation reaction is carried out to obtain a hesperetin p-chlorobenzoyl hydrazone compound. The invention also provides an application of the hesperetin hydrazone compound in preparation of an anti-tumor medicine. It shows through anti-tumor research results that p-chlorobenzoyl hydrazone obtained by chemical modification has a good anti-tumor effect.
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Paragraph 0024; 0025
(2016/12/16)
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- Hesperetin derivatives: Synthesis and anti-inflammatory activity
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Sixteen novel hesperetin derivatives containing Mannich base moiety were designed and synthesized and their anti-inflammatory activities were evaluated by inhibiting tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in mouse RAW264.7 macrophages. Compounds 3a-3k showed better hydrophilic, while compounds 3l-3p with aromatic groups was hydrophobic. The anti-inflammatory activity of title compounds was correlated with log P values, among them, compounds 3c, 3e and 3i with minus log P values exhibited best anti-inflammatory activity through decreasing both IL-6 and TNF-α. Furthermore, the expression of LPS-induced notch1 and inos was reduced by compounds 3c, 3e, and 3i, and compound 3e attenuated LPS-induced inos protein levels in a dose-dependent manner.
- Wang, Qian-Qian,Shi, Jing-Bo,Chen, Chen,Huang, Cheng,Tang, Wen-Jian,Li, Jun
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p. 1460 - 1465
(2016/02/19)
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- Preparation method of flavone aglycone or monoglycoside from aluminum-salt-flavonoid-glycoside complex through hydrolysis
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Disclosed is a preparation method of flavone aglycone or monoglycoside from aluminum-salt-flavonoid-glycoside complex through hydrolysis. The problems that flavonoid glycosides neither dissolve in water nor are hard to dissolve in a common organic alcohol solution, and flavone aglycone prepared from hydrolysis has slow hydrolysis speed, needs a large amount of an organic solvent, and cannot be totally hydrolyzed are solved. A complex product from complexation of aluminum salt and flavonoid glycosides is easy to dissolve in alcohol, hydrogen chloride generated by the complex product is utilized with addition of hydrochloric acid or sulfuric acid, and hydrolysis is carried out at a certain temperature to prepare aglycone or a mixture of aglycone and monoglycoside. After the reaction is over, phosphoric acid or phosphate is added to break complexation of aluminum ions and flavone to obtain flavone aglycone, or the mixture of flavone aglycone and flavone monoglycoside, or a mixture of flavone aglycone, flavone monoglycoside, and flavonoid glycoside. The method is simple and easy to operate, relatively high in yield and purity, and extremely low in cost, and is suitable for massive industrial production of flavone aglycone or the mixture of flavone aglycone and flavone monoglycoside.
- -
-
Paragraph 0014
(2016/10/31)
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- Enzymatic production of oroxylin A and hispidulin using a liverwort flavone 6-O-methyltransferase
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Oroxylin A and hispidulin, compounds which are abundant in both Scutellaria and liverwort species, are important lead compounds for the treatment of ischemic cerebrovascular disease. Their enzymatic synthesis requires an O-methyltransferase able to interact with the related flavonoid's 6-OH group, but such an enzyme has yet to be identified in plants. Here, the gene encoding an O-methyltransferase (designated PaF6OMT) was isolated from the liverwort species Plagiochasma?appendiculatum. A test of alternative substrates revealed that its strongest preferences were baicalein and scutellarein, which were converted into, respectively, oroxylin A and hispidulin. Allowed a sufficient reaction time, the conversion rate of these two substrates was, respectively, 90% and 100%. PaF6OMT offers an enzymatic route to the synthesis of oroxylin A and hispidulin.
- Zhang, Yu-Ying,Xu, Rui-Xue,Gao, Shuai,Cheng, Ai-Xia
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p. 2619 - 2628
(2017/01/14)
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- α-L-Rhamnosyl-β-D-glucosidase (rutinosidase) from Aspergillus niger: Characterization and synthetic potential of a novel diglycosidase
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We report the first heterologous production of a fungal rutinosidase (6-O-α-L-rhamnopyranosyl-β-D-glucopyranosidase) in Pichia pastoris. The recombinant rutinosidase was purified from the culture medium to apparent homogeneity and biochemically characterized. The enzyme reacts with rutin and cleaves the glycosidic linkage between the disaccharide rutinose and the aglycone. Furthermore, it exhibits high transglycosylation activity, transferring rutinose from rutin as a glycosyl donor onto various alcohols and phenols. The utility of the recombinant rutinosidase was demonstrated by its use for the synthesis of a broad spectrum of rutinosides of primary (saturated and unsaturated), secondary, acyclic and phenolic alcohols as well as for the preparation of free rutinose. Moreover, the α-L-rhamnosidase-catalyzed synthesis of a chromogenic substrate for a rutinosidase assay - para-nitrophenyl β-rutinoside - is described.
- imkov, Daniela,Kotik, Michael,Weignerov, Lenka,Halada, Petr,Pelantov, Helena,Adamcov, Kateina,Ken, Vladimr
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supporting information
p. 107 - 117
(2015/01/30)
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- Hydrolysis of scutellarin and related glycosides to scutellarein and the corresponding aglycones
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Scutellarein has been prepared by the hydrolysis of scutellarin with sulfuric acid to provide this biologically important rare flavone in up to > 90% yield and on the 5 g scale in minutes. This protocol has been applied to five other flavonoid glycosides (rutin, hesperidin, naringin, baicalin and diosmin) which are readily hydrolysed to their corresponding aglycones.
- Zhang, Wei,Yi, Dong,Gao, Kai,Liu, Manshuo,Yang, Jian,Liao, Xiali,Yang, Bo
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p. 396 - 398
(2014/08/05)
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- Synthesis and anticholinesterase inhibitory activity of mannich base derivatives of flavonoids
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Hesperidin-derived 2'-hydroxy-3,4,4',6'-tetramethoxy-chalcone and 5-hydroxy-7,3',4'-trimethoxy-flavone underwent reaction with formaldehyde and a series of secondary amines producing 11 new Mannich base derivatives of flavonoids. The aminomethylation occurred preferentially at the C-3' position of the chalcone and at the C-6 position of flavone. These aminated derivatives of flavonoids were evaluated as inhibitors of acetylcholinesterase (AChE) and the results showed that two of them exhibited excellent AChE inhibitory activity.
- Duan, Keke,Liu, Haoran,Fan, Haoqun,Zhang, Jing,Wang, Qiuan
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p. 443 - 446
(2014/08/05)
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- Semisynthesis of polymethoxyflavonoids from naringin and hesperidin
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Polymethoxyflavonoids (PMFs) possess important biological activities, notably as anticancer agents. Semisynthesis of a series of PMFs were performed by glycoside hydrolysis, dehydrogenation, bromination, aromatic nucleophilic substitution, O-methylation, dimethyldioxirane oxidation and regioselective demethylation, starting from abundant and inexpensive natural sources naringin and hesperidin. A new synthetic method for selective methylation using CuBr catalysed and microwave-assisted reaction was developed, and the dimethyl dioxirane oxidation of flavones to flavonols was much improved. The new semisynthetic route has the advantages of easy availability of starting materials, simple operation and good yields.
- Li, Yue,Cai, Shuanglian,He, Kailin,Wang, Qiuan
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p. 287 - 290
(2014/06/09)
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- Purification and characterization of a naringinase from Aspergillus aculeatus JMUdb058
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A naringinase from Aspergillus aculeatus JMUdb058 was purified, identified, and characterized. This naringinase had a molecular mass (MW) of 348 kDa and contained four subunits with MWs of 100, 95, 84, and 69 kDa. Mass spectrometric analysis revealed that the three larger subunits were β-d-glucosidases and that the smallest subunit was an α-l-rhamnosidase. The naringinase and its α-l-rhamnosidase and β-d-glucosidase subunits all had optimal activities at approximately pH 4 and 50 C, and they were stable between pH 3 and 6 and below 50 C. This naringinase was able to hydrolyze naringin, aesculin, and some other glycosides. The enzyme complex had a Km value of 0.11 mM and a kcat/Km ratio of 14 034 s-1 mM -1 for total naringinase. Its α-l-rhamnosidase and β-d-glucosidase subunits had Km values of 0.23 and 0.53 mM, respectively, and kcat/Km ratios of 14 146 and 7733 s -1 mM-1, respectively. These results provide in-depth insight into the structure of the naringinase complex and the hydrolyses of naringin and other glycosides.
- Chen, Yuelong,Ni, Hui,Chen, Feng,Cai, Huinong,Li, Lijun,Su, Wenjin
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p. 931 - 938
(2013/08/24)
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- Transglycosylation specificity of Acremonium sp. α-rhamnosyl-β- glucosidase and its application to the synthesis of the new fluorogenic substrate 4-methylumbelliferyl-rutinoside
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Transglycosylation potential of the fungal diglycosidase α-rhamnosyl-β-glucosidase was explored. The biocatalyst was shown to have broad acceptor specificity toward aliphatic and aromatic alcohols. This feature allowed the synthesis of the diglycoconjugated fluorogenic substrate 4-methylumbelliferyl-rutinoside. The synthesis was performed in one step from the corresponding aglycone, 4-methylumbelliferone, and hesperidin as rutinose donor. 4-Methylumbelliferyl-rutinoside was produced in an agitated reactor using the immobilized biocatalyst with a 16% yield regarding the sugar acceptor. The compound was purified by solvent extraction and silica gel chromatography. MALDI-TOF/TOF data recorded for the [M+Na]+ ions correlated with the theoretical monoisotopic mass (calcd [M+Na]+: 507.44 m/z; obs. [M+Na]+: 507.465 m/z). 4-Methylumbelliferyl-rutinoside differs from 4-methylumbelliferyl-glucoside in the rhamnosyl substitution at the C-6 of glucose, and this property brings about the possibility to explore in nature the occurrence of endo-β-glucosidases by zymographic analysis.
- Mazzaferro, Laura S.,Pi?uel, Lucrecia,Erra-Balsells, Rosa,Giudicessi, Silvana L.,Breccia, Javier D.
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scheme or table
p. 69 - 75
(2012/02/05)
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- Quantification of hesperidin in citrus-based foods using a fungal diglycosidase
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A simple enzymatic-spectrophotometric method for hesperidin quantification was developed by means of a specific fungal enzyme. The method utilises the diglycosidase α-rhamnosyl-β-glucosidase (EC 3.2.1.168) to quantitatively hydrolyse hesperidin to hesperetin, and the last is measured by its intrinsic absorbance in the UV range at 323 nm. The application of this method to quantify hesperidin in orange (Citrus sinensis) juices was shown to be reliable in comparison with the standard method for flavonoid quantification (high performance liquid chromatography, HPLC). The enzymatic method was found to have a limit of quantification of 1.8 μM (1.1 mg/L) hesperidin, similar to the limit usually achieved by HPLC. Moreover, it was feasible to be applied to raw juice, without sample extraction. This feature eliminated the sample pre-treatment, which is mandatory for HPLC, with the consequent reduction of the time required for the quantification.
- Mazzaferro, Laura S.,Breccia, Javier D.
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scheme or table
p. 2338 - 2344
(2012/08/28)
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- Synthesis and anti-hyperglycemic activity of hesperidin derivatives
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A series of hesperidin derivatives were prepared and identified by IR, 1H NMR, and MS spectra. These compounds were evaluated in vitro and in vivo based on α-glucosidase inhibition, glucose consumption of HepG2 cells, and blood glucose level in streptozotocin-induced diabetic mice. The results revealed that all the compounds exhibited anti-hyperglycemic activities. The inhibition at 10-3 M of compounds 3 and 7a on α-glucosidase were 55.02% and 53.34%, respectively, as compared to 54.80% by acarbose. Treated by compound 3 and the reference drug metformin, glucose consumption of HepG2 cell were 1.78 and 2.11 mM, respectively. After the streptozotocin-induced diabetic mice were oral administrated with compound 3 at 100 mg kg-1 d-1 for 10 days, the blood glucose level of 3 treated mice (13.23 mM, P 0.05) showed significant difference when compared to model control (23.03 mM). Thus, compound 3 exhibited promising anti-hyperglycemic activity.
- Zhang, Baoshun,Chen, Tingting,Chen, Zhu,Wang, Mingxue,Zheng, Dengyu,Wu, Jinfeng,Jiang, Xiaofei,Li, Xuegang
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supporting information
p. 7194 - 7197
(2013/01/15)
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- Chemical composition and biological activity of Citrus jambhiri Lush
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The fresh peel of Citrus jambhiri was extracted with aqueous methanol and the residue was fractionated using light petroleum, chloroform and ethyl acetate. The constituents of the extracts were separated by column chromatography employing solvents of different polarity. The chemical structure of the isolated compounds was then identified by MS and NMR. Column chromatography of the petroleum fraction resulted in the isolation of nobiletin, 5-O-demethylnobiletin, tangeretin, 5-hydroxy-3,6,7,8,3′,4′- hexamethoxyflavone, 3,5,6,7,8,3′,4′-heptamethoxyflavone, and a mixture of β-sitosterol and stigmasterol. The chloroform fraction afforded 6-demethoxynobiletin, 5,4′-dihydroxy-6,7,8,3′-tetramethoxyflavone, limonin and nomilin. The flavonoid glycosides naringin, hesperidin and neohesperidin were isolated from the ethyl acetate fraction. The chemical structure of the isolated compounds was established by MS and NMR (APT, COSY, HSQC, HMBC, and NOESY). LC-ESI-MS analysis of the ethyl acetate fraction afforded eight flavonoid glycosides, while the dichloromethane fraction of the defatted seeds contained seven limonoid aglycones. The chloroform fraction exerted the strongest DPPH* free radical scavenging activity in comparison to other fractions. The petroleum fraction showed a significant inhibition of lipoxygenase indicating an anti-inflammatory action (IC50 29 ± 1 μg/mL). Some of the isolated polymethoxyflavones exhibited strong cytotoxicity against COS7, HeLa and Caco-2 cell lines.
- Hamdan, Dalia,El-Readi, Mahmoud Zaki,Tahrani, Ahmad,Herrmann, Florian,Kaufmann, Dorothea,Farrag, Nawal,El-Shazly, Assem,Wink, Michael
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p. 394 - 403
(2013/01/09)
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- α-Rhamnosyl-β-glucosidase-catalyzed reactions for analysis and biotransformations of plant-based foods
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Most aroma compounds exist in vegetal tissues as disaccharide conjugates, rutinose being an abundant sugar moiety in grapes. The availability of aroma precursors would facilitate analytical analysis of plant-based foods. The diglycosidase α-rhamnosyl-β-glucosidase from Acremonium sp. DSM 24697 efficiently transglycosylated the rutinose moiety from hesperidin to 2-phenylethanol, geraniol, and nerol in an aqueous-organic biphasic system. 2-Phenethyl rutinoside was synthesized up to millimolar level with an 80% conversion regarding the donor hesperidin. The hydrolysis of the synthesized aroma precursors was not detected in an aqueous medium. However, in the presence of ethanol as a sugar acceptor, the enzyme was able to transfer the disaccharide residue forming the alkyl-rutinoside. The aroma precursors were significantly hydrolyzed (up to 3-4% in 2 h at 30 °C), which indicated the potential use of the enzyme for biotechnological applications, for example, in aroma modulation of fermented foods.
- Minig, Marisol,Mazzaferro, Laura S.,Erra-Balsells, Rosa,Petroselli, Gabriela,Breccia, Javier D.
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experimental part
p. 11238 - 11243
(2012/03/08)
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- Flavonoids with an oligopolysulfated moiety: A new class of anticoagulant agents
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Polysulfated (oligo)flavonoids were synthesized and assayed for their in vitro and in vivo anticoagulant activities. The approach was based on molecular hybridization of two classes of anticoagulants, sulfated polysaccharides and sulfated flavonoids. The synthesis was optimized using microwave-assisted sulfation with triethylamine-sulfur trioxide. The obtained polysulfated flavonosides were highly effective in increasing clotting times and able to completely block the clotting process, in contrast to their corresponding aglycones. The thromboelastography proved that polysulfated flavonosides possess good whole blood anticoagulation activity. The following structure-activity relationships were found: 3-O-rutinosides (10, 13) were direct inhibitors of FXa, while 7-O-rutinosides (7, 8) showed inhibition of FXa by ATIII activation. Furthermore, compounds 7 and 13 were stable in plasma and active in vivo and preliminary toxicity studies would lead us to rule out acute side effects. From the overall results, the polysulfated flavonosides showed the potential as new effective and safe agents for anticoagulant therapy.
- Correia-Da-Silva, Marta,Sousa, Emília,Duarte, Bárbara,Marques, Franklim,Carvalho, Félix,Cunha-Ribeiro, Luís M.,Pinto, Madalena M. M.
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supporting information; experimental part
p. 95 - 106
(2011/03/20)
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- Synthesis and antimicrobial activity of 7-alkoxyhesperetin derivatives
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Some new 7-alkoxyhesperetin derivatives, 7-methoxy-(c), 7-butoxy-(d), 7-octyloxy-(e), 7-decyloxy- (f), and 7-dodecyloxyhesperetin(g), were synthesized and confirmed by UV, IR, 1H NMR, and MS spectra data. The series of the synthesized compounds has been screened for their antibacterial activity in vitro and evaluated their structure-activity relationships. Substitution of the H with alkyl groups at C-7-OH led to significant change of their antibacterial activity. The antibacterial activity of 7-alkoxyhesperetin derivatives increased with the elongating of the length of aliphatic chain, and the maximum activity was reached at twelve carbon atoms. Compound f showed the highest antibacterial activity among all the compounds. Springer Science+Business Media, LLC 2010.
- Zhang, Baoshun,Ye, Xiaoli,Chen, Zhu,Jiang, Xiaofei,Yuan, Lujiang,Yi, Jun,Li, Xuegang
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experimental part
p. 1200 - 1205
(2012/06/04)
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- Active Compound Combinations
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Compositions comprising a (A) dithiino-tetracarboximide of formula (I) and at least one agriculturally beneficial biological control agent (B) are disclosed. A method for curatively or preventively controlling phytopathogenic fungi of plants or crops is disclosed. A method for treating seed and a method for protecting seed are disclosed.
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- Operational stabilization of fungal α-rhamnosyl-β-glucosidase by immobilization on chitosan composites
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The diglycosidase α-rhamnosyl-β-glucosidase from Acremonium sp. DSM24697 was immobilized by adsorption and cross-linking. The supports screened included beads of chitosan composites (gelatin, arabic gum, silica gel), epoxy-activated agarose and chitosan, and macroporous polyvinyl-alcohol cryogel. The chitosan-silica gel beads were selected because of the highest immobilization efficiency obtained and their morphological properties (diameter 1.67 ± 0.99 mm, circularity 0.81 ± 0.05). The optimization of the immobilization - coating with polyethyleneimine, changes in the enzyme load - improved the immobilization efficiency up to 18%. The practical use of the enzyme deals with low water solubility substrates. The higher KM for the immobilized enzyme - 8 mM vs. 1.8 mM hesperidin for the free enzyme - indicated that substrate diffusion limits the enzymatic reaction. The solvent dimethylsulfoxide (50%, v/v) was added in order to increase the substrate solubility, and 80% activity was retained (1 h, 60 °C) in contrast with the complete inactivation of the free form. The stability of the immobilized catalyst was extended to metal catalyzed oxidation where the enzyme was fully preserved in harsh conditions such as 1 mM CuSO4 at 60 °C during 1 h.
- Pi?uel, Lucrecia,Mazzaferro, Laura S.,Breccia, Javier D.
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experimental part
p. 2330 - 2335
(2012/05/20)
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- Stereoselective conjugation, transport and bioactivity of S- and R-hesperetin enantiomers in vitro
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The flavanone hesperetin ((±)-4′-methoxy-3′,5,7- trihydroxyflavanone) is the aglycone of hesperidin, which is the major flavonoid present in sweet oranges. Hesperetin contains a chiral C-atom and so can exist as an S- and R-enantiomer, however, in nature 2S-hesperidin and its S-hesperetin aglycone are predominant. The present study reports a chiral HPLC method to separate S- and R-hesperetin on an analytical and semipreparative scale. This allowed characterization of the stereoselective differences in metabolism and transport in the intestine and activity in a selected bioassay of the separated hesperetin enantiomers in in vitro model systems: (1) with human small intestinal fractions containing UDP-glucuronosyl transferases (UGTs) or sulfotransferases (SULTs); (2) with Caco-2 cell monolayers as a model for the intestinal transport barrier; (3) with mouse Hepa-1c1c7 cells transfected with human EpRE-controlled luciferase to test induction of EpRE-mediated gene expression. The results obtained indicate some significant differences in the metabolism and transport characteristics and bioactivity between S- and R-hesperetin, however, these differences are relatively small. This indicates that for these end points, including intestinal metabolism and transport and EpRE-mediated gene induction, experiments performed with racemic hesperetin may adequately reflect what can be expected for the naturally occurring S-enantiomer. This is an important finding since at present hesperetin is only commercially available as a racemic mixture, while it exists in nature mainly as an S-enantiomer.
- Brand, Walter,Shao, Jia,Hoek-Van Den Hil, Elisabeth F.,Van Elk, Kathelijn N.,Spenkelink, Bert,De Haan, Laura H. J.,Rein, Maarit J.,Dionisi, Fabiola,Williamson, Gary,Van Bladeren, Peter J.,Rietjens, Ivonne M. C. M.
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experimental part
p. 6119 - 6125
(2011/08/05)
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- Aroma Composition to Reduce or Suppress Undesirable Bitter and Astringent Taste Impressions of Sweeteners
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The invention concerns an aroma composition to reduce or suppress a bitter or astringent impression in the oral cavity, comprising (i) one or more sweeteners and (ii) one or more specific bitter-masking aroma substances and/or flavourings and optionally (iii) one or more sweetness intensifying aroma substances and/or sweeteners and optionally (iv) one or more inactive substances or carriers. The invention also concerns a preparation, containing such an aroma composition, the use of an aroma composition for reducing or eliminating a bitter and astringent effect of an artificial sweetener and a corresponding method for reducing or eliminating the bitter and astringent effect of a sweetener.
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- Statin-like principles of bergamot fruit (Citrus bergamia): Isolation of 3-hydroxymethylglutaryl flavonoid glycosides
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The 3-hydroxy-3-methylglutaryl neohesperidosides of hesperetin (brutieridin, 1) and naringenin (melitidin, 2) were isolated and detected from the fruits of bergamot (Citrus bergamia). The structures of these compounds were determined by spectroscopic and
- Di Donna, Leonardo,De Luca, Giuseppina,Mazzotti, Fabio,Napoli, Anna,Salerno, Raffaele,Taverna, Domenico,Sindona, Giovanni
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supporting information; experimental part
p. 1352 - 1354
(2009/12/29)
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- In vivo pharmacokinetics of hesperidin are affected by treatment with glucosidase-like BglA protein isolated from yeasts
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Hesperidin is an abundant flavanone glycoside in citrus fruits and has been reported to possess a wide range of biological activities. However, hesperidin has poor bioavailability. Here, we tested the hypothesis that hesperetin found in chenpi will have a better bioavailability than hesperidin and that treatment of hesperidin with the glucosidase-like yeast Bg1A protein will increase its bioavailability. The results indicate that hesperidin in pure or extract form is hydrolyzed by BglA protein extracted from Sporobolomyces singularis or expressed in Escherichia coli BL21 (DE3). This biotransformation affected the plasma pharmacokinetics of total hesperetin in rats, in that the plasma T max was significantly shorter after administration of BglA protein-treated hesperidin than after administration of hesperidin extract. In addition, the area under the curve values for total hesperetin after administration of Bg1A-treated hesperidin were ～4-fold higher by oral administration and 3-fold higher by intravenous administration, respectively. In contrast, the plasma clearance value and volume of distribution after administration of Bg1A-treated hesperidin extract or pure hesperetin were significantly smaller than after administration of untreated hesperidin extract or pure hesperidin. This is the first study that systemically determines the absolute bioavailability of hesperidin and hesperetin simultaneously, shows clearly that hesperetin is more bioavailable than hesperidin regardless of the route of administration, and shows that prior transformation of hesperidin to hesperetin via fermentation should significantly increase its bioavailability because of the action of the yeast glycosidase-like protein BglA.
- Li, Yong-Mei,Li, Xiao-Mian,Li, Guang-Ming,Du, Wen-Cai,Zhang, Jing,Li, Wei-Xia,Xu, Jianshe,Hu, Ming,Zhu, Ze
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experimental part
p. 5550 - 5557
(2010/03/30)
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- Long-lasting absorption of flavonoids
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The present invention relates to methods for a long-term and sustained release of flavonoids, in particular rhamnose-containing flavonoids, and for prolonging the uptake of said flavonoids in the gastro-intestinal tract. It further relates to compositions comprising said flavonoid and α-rhamnosidase. It also encompasses compositions comprising hesperidin and hesperetin-7-glucoside.
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Page/Page column 6; 7
(2008/06/13)
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- Bioavailability of glucosyl hesperidin in rats
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Glucosyl hesperidin (G-hesperidin) is a water-soluble derivative of hesperidin. We compared the absorption and metabolism of G-hesperidin with those of hesperidin in rats. After oral administration of G-hesperidin or hesperidin to rats, hesperetin was detected in sera hydrolyzed with β-glucuronidase, but it was not detectable in unhydrolyzed sera. Serum hesperetin was found more rapidly in rats administered G-hesperidin than in those administered hesperidin. The area under the concentration-time curve for hesperetin in the sera of rats administered G-hesperidin was approximately 3.7-fold greater than that of rats administered hesperidin. In the urine of both administration groups, hesperetin and its glucuronide were found. Urinary excretion of metabolites was higher in rats administered G-hesperidin than in those administered hesperidin. These results indicate that G-hesperidin presents the same metabolic profile as hesperidin. Moreover, it was concluded that G-hesperidin is absorbed more rapidly and efficiently than hesperidin, because of its high water solubility.
- Yamada, Mika,Tanabe, Fujimi,Arai, Norie,Mitsuzumi, Hitoshi,Miwa, Yoshikatsu,Kubota, Michio,Chaen, Hiroto,Kibata, Masayoshi
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p. 1386 - 1394
(2008/02/11)
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- New potent antioxidative hydroxyflavanones produced with Aspergillus saitoi from flavanone glycoside in citrus fruit.
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Potent antioxidative hydroxyflavanones were produced with Aspergillus saitoi from hesperidin or naringin, which are flavanone glycosides in citrus fruit with weak antioxidative activity. The hydroxyflavanone produced from hesperidin was identified as 8-hydroxyhesperetin (8-HHE), a novel substance, and those from naringin were identified as carthamidin (6-hydroxynaringenin) and isocarthamidin (8-hydroxynaringenin) by FAB-MS, 1H-NMR and 13C-NMR analyses. The antioxidative activity of these hydroxyflavanones was examined by using the free radical-scavenging system of 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the methyl linoleate oxidation system. The hydroxyflavanones (8-HHE, carthamidin, and isocarthamidin) exhibited stronger activity than the flavanone glycosides (hesperidin or naringin) and their aglycones (hesperetin or naringenin). The activity of 8-HHE and isocarthamidin was comparable to that of alpha-tocopherol, and that of carthamidin was weaker than that of isocarthamidin. The hydroxyflavanones, which were hydroxylated on A ring of flavanone by Aspergillus saitoi, were obtained as potent antioxidants.
- Miyake, Yoshiaki,Minato, Kenichiro,Fukumoto, Syuichi,Yamamoto, Kanefumi,Oya-Ito, Tomoko,Kawakishi, Syunro,Osawa, Toshihiko
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p. 1443 - 1450
(2007/10/03)
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- Novel use of flavones
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A pharmaceutical composition for inhibiting COX-2 biosynthesis comprising a therapeutically effective amount of the compound of formula I and a pharmaceutrically acceptable carrier. wherein R1 and R4 represent either Hydrogen or together a bond R5, R6, R7, R8 represent independently of each other Hydrogen, Hydroxy or Methoxy; in addition R7 represents a sugar substituent like glucoside, rutinosid, manno gluco pyransyl, aprosylglucoside R2 and R3 represent Hydrogen, Hydroxy, Methoxy or wherein R2′, R3′, R4′, R5′ and R6′ are independently or each other Hydrogen, Hydroxy or Methoxy with the proviso, that R2 or R3 is represented by the optionally substituted Phenylring.
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- Acid-catalyzed hydrolysis of hesperidin at elevated temperatures
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Dilute sulfuric acid was used as a catalyst for hydrolysis of hesperidin suspensions in water at temperatures ranging from 25 to 180 °C. Significant acceleration of the reaction was observed at 120 °C and higher temperatures. This increase in the rate of hydrolysis can be attributed to increased solubilization of hesperidin in water at higher temperatures. Partial hydrolysis of hesperidin at 140 °C was used for the preparations of hesperetin-7-glucoside, which has a value in the synthesis of dihydrochalcone sweeteners. Simple separation of hesperetin and hesperetin-7-glucoside by extraction with dry acetone or lower alcohols has been developed. (C) 2000 Elsevier Science Ltd.
- Grohmann, Karel,Manthey, John A.,Cameron, Randall G.
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p. 141 - 146
(2007/10/03)
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- Flavanone glycosides from Alhagi pseudalhagi
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Two new flavanone glycosides, alhagitin and alhagidin, have been isolated from the whole plant of Alhagi pseudalhagi and their structures established respectively as naringenin 5-methyl ether 4'-glucoside and hesperitin 7-galactosyl(1 → 2)[rhamnosyl(1 → 6)]glucoside by chemical and spectroscopic methods.
- Singh,Yadav, Bineeta,Pandey
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p. 587 - 590
(2007/10/03)
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- Flavonoids as antioxidants
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Spectral, acid-base, and redox properties of the phenoxyl radicals derived from 3,4-dihydroxybenzene derivatives and selected flavonoids were studied by pulse radiolysis of aqueous solutions. From the pH-dependent changes in the phenoxyl spectra, the dissociation constants were derived. The pK(a) values for the deprotonation of the 3'-OH group in the catechin (pK(a) = 4.6) and rutin (pK(a) = 4.3) radicals are similar to the pK(a) value of the 3,4-dihydroxybenzoate radicals, pK(a) = 4.2, which is expected from their similar electronic structures. Deprotonation of 5- and 7-OH in the catechin and rutin and of 5-OH in the hesperidin radicals has no effect on the radical spectra, which is explained by the inefficient coupling of the A-ring of the flavonoid radicals with the unpaired electron. Because of favorable reduction potentials of the phenoxyl radicals, E7 = 0.56-0.7 V vs NHE, flavonoids may act as efficient antioxidants of alkylperoxyl and superoxide/hydroperoxyl radicals. The ac kinetic conductivity method was developed for the measurements of the low reaction rate constants of the superoxide radical reactions with flavonoids and phenols in aqueous solutions at pH 10. The rates of the superoxide radical reactions with flavonoids, k = 3 x 102-5.1 x 104 M-1 s-1, depend on the redox properties and the charge of the flavonoids. The highest rates are measured for the oxidation of quercetin and rutin, whereas the lowest are those for the B-ring monosubstituted derivatives, with substantially higher redox potentials. Uncharged catechin at pH 7 reacts at k = 6.6 x 104 M-1 s-1, whereas the rate at pH 10, where catechin is doubly negatively charged, is approximately 4 times lower, k = 1.8 x 104 M-1 s-1. The activation parameters of the oxidation of rutin and trolox at pH 10 and methylgallate at pH 7 were determined in an attempt to understand why the rates of the superoxide reactions are low despite high driving forces of ΔE ≥ 0.4 V. Low activation enthalpies, ΔH(paragraph) 2.3-3.6 kcal/mol, and negative activation entropies, ΔS(paragraph) = -25-28 cal/(mol K), point to an inner-sphere electron-transfer mechanism.
- Jovanovic, Slobodan V.,Steenken, Steen,Tosic, Mihajlo,Marjanovic, Budimir,Simic, Michael G.
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p. 4846 - 4851
(2007/10/02)
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- Conversion of hesperidin into hesperetin
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An improved procedure for the conversion of commercial hesperidin into high-purity, crystalline hesperetin is disclosed. This procedure comprises purifying the crude starting material by insolubles removal and precipitation, followed by cleaving the saccharides with a strong mineral acid in lower primary alkanol. The use of lower alkanol in this transformation facilitates the isolation of a high purity product uncontaminated by resinified sugars.
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