Aglycone Derivatives Research Articles

Synthesis, bioactivities and 3D-QSAR of novel avermectin B2a aglycon derivatives

Fourteen avermectin B2a aglycon derivatives were designed and synthesized after removing the oleandrose disaccharide of avermectin B2a. Their structures were characterized by 1H NMR, 13C NMR, HMRS. Preliminary bioassays indicated that these compounds exhibited good insecticidal activity against diamondback moth at 200 mg/L, with mortality no less than 90%. Compounds 10b, 12a, 12c, 17 demonstrated good acaricidal activity against the adult mites, larvae, and good inhibition rate of hatching to mite eggs of Tetranychus cinnabarinus. Compounds 5, 10b, 10c exhibited excellent fungicidal activity against fourteen fungal pathogens in vitro. 3D-QSAR analysis showed that the fungicidal activity of avermectin B2a aglycon derivatives would be increased when a negatively charged and bulky group was introduced at 13-position, which will be instructive for the further modification of avermectin B2a aglycon.

Formation of Nudicaulins In Vivo and In Vitro and the Biomimetic Synthesis and Bioactivity of O-Methylated Nudicaulin Derivatives.

Nudicaulins are yellow flower pigments accounting for the color of the petals of Papaver nudicaule (Papaveraceae). These glucosidic compounds belong to the small group of indole/flavonoid hybrid alkaloids. Here we describe in vivo and in vitro experiments which substantiate the strongly pH-dependent conversion of pelargonidin glucosides to nudicaulins as the final biosynthetic step of these alkaloids. Furthermore, we report the first synthesis of nudicaulin aglycon derivatives, starting with quercetin and ending up at the biomimetic fusion of a permethylated anthocyanidin with indole. A small library of nudicaulin derivatives with differently substituted indole units was prepared, and the antimicrobial, antiproliferative and cell toxicity data of the new compounds were determined. The synthetic procedure is considered suitable for preparing nudicaulin derivatives which are structurally modified in the indole and/or the polyphenolic part of the molecule and may have optimized pharmacological activities.

Three Regioselectively Acylated Flavonoid Aglycone Derivatives in Equimolar Yield at One Blow

AbstractA simple and time‐effective chemoenzymatic process to obtain three regioselective acylated quercetin analogues in a 1:1:1 ratio in one pot is described. This process overcomes the inherent scaffold intricacy and synthetic complexity of quercetin. Cell proliferation experiments in three breast cancers cell lines pinpoint the high potency of the generated compounds.

Synthesis of Curcumin Glycosides with Enhanced Anticancer Properties Using One-Pot Multienzyme Glycosylation Technique.

Curcumin is a natural polyphenolic compound, widely acclaimed for its antioxidant, antiinflammatory, antibacterial, and anticancerous properties. However, its use has been limited due to its low-aqueous solubility and poor bioavailability, rapid clearance, and low cellular uptake. In order to assess the effect of glycosylation on the pharmacological properties of curcumin, one-pot multienzyme (OPME) chemoenzymatic glycosylation reactions with UDP- α-D-glucose or UDP-α-D-2-deoxyglucose as donor substrate were employed. The result indicated significant conversion of curcumin to its glycosylated derivatives: curcumin 4'-O-β- glucoside, curcumin 4',4''-di-O-β-glucoside, curcumin 4'-O-β-2-deoxyglucoside, and curcumin 4',4''-di-O-β-2-deoxyglucoside. The products were characterized by ultra-fast performance liquid chromatography, high-resolution quadruple-time-of-flight electrospray ionization-mass spectrometry, and NMR analyses. All the products showed improved water solubility and comparable antibacterial activities. Additionally, the curcumin 4'-O-β-glucoside and curcumin 4'-O-β-2-deoxyglucoside showed enhanced anticancer activities compared with the parent aglycone and diglycoside derivatives. This result indicates that glycosylation can be an effective approach for enhancing the pharmaceutical properties of different natural products, such as curcumin.

Oleuropein shows copper complexing properties and noxious effect on cultured SH-SY5Y neuroblastoma cells depending on cell copper content

The secoiridoid oleuropein is a non-flavonoid polyphenol, found in the fruit, leaves and food derivatives from Olea europea. Like other polyphenols it shows a very low toxicity towards healthy tissues and a protective action against cancer or neurodegeneration, but its mechanism of action is not yet understood. In the present report we have used optical and ESR spectroscopy as well as molecular modelling to demonstrate that oleuropein forms a complex with the transition metal copper; the dysmetabolism of this metal is suspected to be involved in both cancer and neurodegeneration. Experiments carried out with the aglycon derivative of oleuropein, produced by β-glycosidase treatment of oleuropein glycoside, showed that also the aglycon forms copper-complexes, but with different spectroscopic features than the glycosidic form. Molecular modelling analysis confirmed that two oleuropein molecules (glycosidic or aglycon forms) can easily coordinate one copper ion. The relationship between oleuropein and copper was investigated in SH-SY5Y human neuroblastoma cells. When cells were depleted of copper by treatment with the copper chelator triethylenetetramine (Trien), that binds copper with higher affinity than oleuropein, oleuropein was less toxic than to copper-adequate cells. Conversely, incubation of SH-SY5Y cells with exogenous copper sulphate increased cell susceptibility to oleuropein. Furthermore SH-SY5Y cells differentiated by retinoic acid pre-treatment showed a lower level of copper, and were more resistant to oleuropein treatment. The oleuropein aglycon was not toxic towards SH-SY5Y cells. In conclusion, the copper-oleuropein complex may be involved in the toxicity of oleuropein towards tumour cells, depending on their copper level.

Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice

A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600mg/kg xanthine once daily for 7 days and intraperitoneally injected 250mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30mg/kg), allopurinol (20mg/kg) or benzbromarone (20mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti-hyperuricemia agent.

The Ginsenoside Derivative 20(S)-Protopanaxadiol Inhibits Solar Ultraviolet Light-Induced Matrix Metalloproteinase-1 Expression.

Ginsenosides are major pharmacologically active compounds present in ginseng (Panax ginseng). Among the ginsenosides, 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol (GPPD) and ginsenoside Rb1 (Rb1) have previously been reported to exhibit anti-wrinkle effects. In this study, 20(S)-protopanaxadiol (20(S)-PPD), an aglycone derivative of the Rb1 metabolite was investigated for its anti-wrinkle benefit and compared to GPPD and Rb1. The anti-wrinkle effect of 20(S)-PPD during solar UV light was investigated using a human skin equivalent model and human keratinocytes. 20(S)-PPD attenuated solar UV-induced matrix metalloproteinase (MMP)-1 expression to a greater extent than GPPD and Rb1. 20(S)-PPD treatment modulated MMP-1 mRNA expression and the transcriptional activity of activator protein (AP)-1, a major transcription factor of MMP-1. Two upstream signaling pathways for AP-1, the MEK1/2-ERK1/2-p90RSK and MEK3/6-p38 pathways, were also suppressed. Taken together, these findings highlight the potential of 20(S)-PPD for further development as a preventative agent for sunlight-induced skin wrinkle. J. Cell. Biochem. 118: 3756-3764, 2017. © 2017 Wiley Periodicals, Inc.

Synthesis and antioxidant evaluation of lipophilic oleuropein aglycone derivatives.

Oleuropein is the most important phenolic compound present in olive cultivars, but it is scarcely present in extra virgin olive oil (EVOO) due to its high hydrophilicity and degradability. Thus, a set of oleuropein aglycone derivatives were synthesized by transacetylation under mild conditions with the aim of circumventing these drawbacks and making the active moiety in oleuropein suitable to be added to food fats. The oleuropein aglycone (closed ring form) is obtained by hydrolyzing oleuropein using Lewis acid catalysis. Then, the permeation profiles as well as the antioxidant capacity of the oleuropein aglycone derivatives were evaluated by ORAC, DPPH assays and by ROS formation using the SH-SY5Y cell line. The biological activities of the obtained compounds exhibited a dependence on their level of lipophilicity.

Degradation of vicine, convicine and their aglycones during fermentation of faba bean flour.

In spite of its positive repercussions on nutrition and environment, faba bean still remains an underutilized crop due to the presence of some undesired compounds. The pyrimidine glycosides vicine and convicine are precursors of the aglycones divicine and isouramil, the main factors of favism, a genetic condition which may lead to severe hemolysis after faba bean ingestion. The reduction of vicine and convicine has been targeted in several studies but little is known about their degradation. In this study, the hydrolysis kinetics of vicine and convicine and their derivatives during fermentation with L. plantarum DPPMAB24W was investigated. In particular, a specific HPLC method coupled to ESI-MS and MS/MS analysis, including the evaluation procedure of the results, was set up as the analytical approach to monitor the compounds. The degradation of the pyrimidine glycosides in the fermented flour was complete after 48 h of incubation and the aglycone derivatives could not be detected in any of the samples. The toxicity of the fermented faba bean was established through ex-vivo assays on human blood, confirming the experimental findings. Results indicate that mild and cost effective bioprocessing techniques can be applied to detoxify faba bean also for industrial applications.

The possible presence of natural β-d-glucosidase inhibitors in jujube leaf extract

Isoquercitrin is a phenolic compound well-known for having greater health benefits than quercitin, its aglycone derivative, and other related glycosides. However, isoquercitrin is rarely found in nature. Here, we optimized the conditions for the enzymatic transformation of isoquercitrin from rutin that was extracted from jujube leaf using the hesperidinase, enzyme complex containing β-d-glucosidase and α-l-rhamnosidase. The maximum productivity (2.57±0.16mg/mL) was experimentally found under the following conditions: 47.3°C, 52.16h, and pH 5.31, which agreed well with the predicted value (2.65mg/mL). However, the achievement of this maximum yield was due to the absence of β-d-glucosidase activity. Further investigations using a β-d-glucosidase assay and reaction measurements under various conditions revealed that the β-d-glucosidase activity was not blocked by denaturation or known inhibitory factors. Currently, there are no recognized β-d-glucosidase inhibitors present in the jujube leaf; however, our observations strongly suggest that an unidentified β-d-glucosidase inhibitor exists in jujube leaf extract.

Total syntheses and initial evaluation of [Ψ[C(═S)NH]Tpg⁴]vancomycin, [Ψ[C(═NH)NH]Tpg⁴]vancomycin, [Ψ[CH₂NH]Tpg⁴]vancomycin, and their (4-chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the glycopeptide antibiotics.

Full details of studies are disclosed on the total syntheses of binding pocket analogues of vancomycin bearing the peripheral L-vancosaminyl-1,2-D-glucosyl disaccharide that contain changes to a key single atom in the residue-4 amide (residue-4 carbonyl O → S, NH, H2) designed to directly address the underlying molecular basis of resistance to vancomycin. Also disclosed are studies piloting the late-stage transformations conducted on the synthetically more accessible C-terminus hydroxymethyl aglycon derivatives and full details of the peripheral chlorobiphenyl functionalization of all of the binding-pocket-modified vancomycin analogues designed for dual D-Ala-D-Ala/D-Ala-D-Lac binding. Their collective assessment indicates that combined binding pocket and chlorobiphenyl peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, and VanA and VanB VRE) and impressive potencies against both vancomycin-sensitive and vancomycin-resistant bacteria (MICs = 0.06-0.005 and 0.5-0.06 μg/mL for the amidine and methylene analogues, respectively) and likely benefit from two independent and synergistic mechanisms of action, only one of which is dependent on D-Ala-D-Ala/D-Ala-D-Lac binding. Such analogues are likely to display especially durable antibiotic activity that is not prone to rapidly acquired clinical resistance.

A few atoms make the difference: Synthetic, CD, NMR and computational studies on antiviral and antibacterial activities of glycopeptide antibiotic aglycon derivatives

Despite the close structural similarity between the heptapeptide cores of the glycopeptide antibiotics teicoplanin and ristocetin, synthetically modified derivatives of their aglycons show significantly different antibacterial and antiviral properties. The teicoplanin aglycon derivatives with one exception proved to be potent antibacterials but they did not exhibit anti-influenza virus activity. In contrast, the aglycoristocetin derivatives generally showed high anti-influenza virus activity and possessed moderate antibacterial activity. A systematic structure-activity relationship study has been carried out on ristocetin and teicoplanin aglycon derivatives, to explore which structural differences are responsible for these markedly different biological activities. According to electronic circular dichroism and in silico conformational studies, it was found that the differences in anti-influenza virus activity are mainly determined by the conformation of the heptapeptide core of the antibiotics controlled by the presence or absence of chloro substituents. Knowledge of the bioactive conformation will help to design new analogs with improved anti-influenza virus activity. For the teicoplanin derivatives, it was shown that derivatization to improve the antiviral efficacy was accompanied by a significant decrease in antibacterial activity.

Melibiose, a non‐digestible saccharide, promotes absorption of quercetin glycosides in rat small intestine with a novel mechanism (1044.9)

We examined effects of melibiose a non‐digestible saccharide, on intestinal absorption of quercetin glycosides, which are low bioavailability but have antioxidant, anti‐inflammatory and anti‐carcinogenic properties. We used water‐soluble quercetin glycosides (a mixture of ~7 glucose adducts of quercetin‐3‐O‐glucoside, Q3GM). Melibiose (150 µmol) with or without Q3GM (15 or 60 µmol) was directly injected into a ligated segment of rat jejunum in anesthetized rats or into the duodenum in conscious rats. Before and after an injection, the concentrations of quercetin derivatives in the portal blood collected through a cannula were measured by LC‐MS. Melibiose enhanced absorption of quercetin aglycon and total quercetin derivative including conjugated and methylated forms in situ experiments. We found a similar tendency in in vivo experiment using portal cannulated rats. Additionaly, we found that Q3GM was very rapidly hydrolyzed to Quercetin‐3‐O‐glucoside (Q3G) by a homogenate of the small intestinal mucosa, but melibiose promoted further hydrolysis of Q3G to quercetin aglycone. In conclusion, non‐digestible saccharides, melibiose, enhances intestinal absorption of quercetin glycosides with increasing hydrolysis to quercetin aglycone in the small intestinal lumen. This study suggests that melibiose contribute health promotive effects of quercetin glycosides.

In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts

Ethnopharmacological relevanceInteractions between conventional drug and traditional medicine therapies may potentially affect drug efficacy and increase the potential for adverse reactions. Cree traditional healing is holistic and patients may use medicinal plants simultaneously with the conventional drugs. However, there is limited information that these medicinal plants may interact with drugs and additional mechanistic information is required. In this study, extracts from traditionally used Cree botanicals were assessed for their potential interaction that could alter the disposition of two blood glucose lowering drugs, gliclazide (Diamicron) and repaglinide (Gluconorm) though inhibition of either metabolism or transport across cell membranes. Materials and methodsThe effect of 17 extracts on metabolism was examined in a human liver microsome assay by HPLC and individual cytochrome P450s 2C9, 2C19, 2C8 and 3A4 in a microplate fluorometric assay. Gliclazide, rhaponticin and its aglycone derivative, rhapontigenin were also examined in the fluorometric assay. The effect on transport was examined with 11 extracts using the intestinal epithelial Caco-2 differentiated cell monolayer model at times up to 180min. ResultsBoth blood glucose lowering medications, gliclazide and repaglinide traversed the Caco-2 monolayer in a time-dependent manner that was not affected by the Cree plant extracts. Incubation of the Cree plant extracts inhibited CYP2C9, 2C19, 2C8 and 3A4-mediated metabolism, and the formation of four repaglinide metabolites: M4, m/z 451-A, m/z 451-B and the glucuronide of repaglinide in the human liver microsome assay. Gliclazide caused no significant inhibition. Likewise, rhaponticin had little effect on the enzymes causing changes of less than 10% with an exception of 17% inhibition of CYP2C19. By contrast, the aglycone rhapontigenin showed the greatest effects on all CYP-mediated metabolism. Its inhibition ranged from a mean of 58% CYP3A4 inhibition to 89% inhibition of CYP2C9. While rhaponticin and the aglycone did not show significant effects on repaglinide metabolism, they demonstrated inhibition of gliclazide metabolism. The aglycone significantly affected levels of gliclazide and its metabolites. ConclusionThese studies demonstrate that the Cree plant extracts examined have the potential in vitro to cause drug interactions through effects on key metabolic enzymes.

Bioavailability of phenolics from an oleuropein-rich olive (Olea europaea) leaf extract and its acute effect on plasma antioxidant status: comparison between pre- and postmenopausal women

Preclinical studies suggest a potential protective effect of oleuropein in osteoporosis, and one of the proposed mechanisms is the modulation of the oxidative stress. Oleuropein bioavailability and its effect on antioxidant status in pre- and postmenopausal women are unknown. The aim of the present study was to investigate the oral bioavailability of an olive leaf extract rich in oleuropein (40 %) and its effect on antioxidant status in postmenopausal women compared to premenopausal women. Premenopausal (n = 8) and postmenopausal women (n = 8) received 250 mg of olive leaf extract, blood samples (t = 0, 1, 2, 3, 4, 6, 8, 12, 16 and 24 h) were taken, and 24-h urine divided into five fractions was collected. Olive-leaf-extract-derived metabolites were analyzed in plasma and urine by HPLC-ESI-QTOF and UPLC-ESI-QqQ, and pharmacokinetics parameters were determined. Ferric reducing antioxidant ability and malondialdehyde levels were measured in plasma. Plasma levels of hydroxytyrosol glucuronide, hydroxytyrosol sulfate, oleuropein aglycon glucuronide and oleuropein aglycon derivative 1 were higher in postmenopausal women. MDA levels were significantly decreased (32%) in postmenopausal women and inversely correlated with hydroxytyrosol sulfate levels. Postmenopausal women excreted less sulfated metabolites in urine than premenopausal women. Our results suggest that postmenopausal women could be a target population for the intake of olive phenolics in order to prevent age-related and oxidative stress-related processes such as osteoporosis.

Flexible synthesis of anthracycline aglycone mimics via domino carbopalladation reactions

A synthesis of anthracycline aglycone derivatives is described. The key step utilizes a powerful domino carbopalladation approach and subsequent ring closure. During this process two of the four rings of the anthracycline scaffold are formed. Differently substituted carbohydrates and dialkyne chains serve as versatile and simple starting materials for the reaction sequence. Diverse building blocks lead to a variety of different products and a broad range of structural diversity.

Probing the Role of the Vancomycin E-Ring Aryl Chloride: Selective Divergent Synthesis and Evaluation of Alternatively Substituted E-Ring Analogues

The selective functionalization of vancomycin aglycon derivatives through conversion of the E-ring aryl chloride to a reactive boronic acid and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described. The series was used to examine the E-ring chloride impact in binding d-Ala-d-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively nonpolar substituents approach or match the chloro-substituted vancomycin and were insensitive to the electronic character of the substituent (e.g., Cl vs CN/OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated vancomycin aglycon derivatives exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the functionalization of a minimally protected vancomycin aglycon (N-Boc-vancomycin aglycon) and provides a direct method for the preparation of previously inaccessible analogues.

Simple and fast determination of phenolic compounds from different varieties of olive oil by nonaqueous capillary electrophoresis with UV-visible and fluorescence detection

In this article, we proposed very simple procedures to analyze important phenolic compounds in olive oil samples from different olive varieties. A nonaqueous CE method has been employed. The main phenolic alcohols in virgin olive oil (tyrosol and hydroxytyrosol) and some among the most abundant secoiridoid aglycone derivatives (dialdehydic form of decarboxymethyl elenoic acid linked to hydroxytyrosol, an isomer of oleuropein aglycone and the dialdehydic form of decarboxymethyl elenoic acid linked to tyrosol) were determined by a direct injection into the capillary of the olive oil dissolved in 1-propanol 1:1 v/v. For the determination of compounds present at lower concentrations, a very simple liquid-liquid extraction method with ethanol has been proposed. The extraction was performed using a relationship 5:1 w/v olive oil/ethanol to achieve the necessary preconcentration of the analytes and the ethanolic extracts were directly injected into the capillary to obtain a very important time reduction. Good recoveries were obtained with both the procedures, using an internal standard. Finally, these procedures were applied to the analysis of these compounds in extra virgin olive oil samples from different varieties of olive.

Effect of Roasting and Boiling on the Content of Vicine, Convicine and L‐3,4‐dihydroxyphenylalanine in Vicia fabaL.

AbstractThe pyrimidine glycosides, vicine and convicine, are compounds of the genus Vicia, whereas their aglycone derivatives, divicine and isouramil, are responsible for favism occurrence, and L‐3,4‐dihydroxyphenylalanine (L‐DOPA) is a nonprotein amino acid precursor of dopamine in healthy neurons. The present work evaluated the effect of thermal treatment, which consisted of roasting and boiling, on the content of vicine, convicine and L‐DOPA in mature cotyledons of 10 varieties of Mexican Vicia faba L. and determined the concentration of glycosides and L‐DOPA by high‐performance liquid chromatography. The raw cotyledons showed 2.88–6.10, 0.63–1.68 and 0.28–0.44 vicine, convicine and L‐DOPA, respectively. The 12 and 40% and 30 and 61% decrease in vicine and convicine content, respectively, were observed to be the effect of roasting and boiling the samples. L‐DOPA was totally removed by both thermal processes. In all analyzed samples, vicine was the main compound; however, there were significant differences between varieties and thermal treatments.Practical ApplicationsVicine and convicine glycosides are strongly implicated in favism, a hemolytic anemia in humans, and in poor performance of laying hens. There are reports of decreased egg weight, increase in the fragility of the yolk and a number of blood stains, and decreased fertility and hatchability of eggs. The characterization of new varieties of faba bean in their content of potentially toxic glycosides allows selection of those with the lowest possible content of such compounds. Also, the application of heat treatments that reduce glycosides will allow the use of seeds or flour to develop harmless food and feed ingredients.

Synthesis of fluorescent ristocetin aglycon derivatives with remarkable antibacterial and antiviral activities

Isoindole and benzoisoindole derivatives of ristocetin aglycon have been prepared by reaction with o-phthalaldehyde or naphthalene-2,3-dialdehyde and various thiols. The new compounds exhibited potent antibacterial and anti-influenza virus activity. The cluster forming and fluorescent properties of the aglycon derivatives were also studied.