Activity-guided fractionation in combination with sensory analytics, LC-TOF-MS, and 1D/2D-NMR spectroscopy enabled the identification of the bitter tasting diarylheptanoids asadanin, giffonin P, and ...the previously not reported ( E)-7,9,10,13-tetrahydroxy-1,7-bis(2-hydroxyphenyl)hept-9-en-11-one and 4,12,16-trihydroxy-2-oxatricyclo13.3.1.1
-nonadeca-1(18),3,5,7(20),8,15,17-heptaen as well as the yet unknown astringent compounds 2-(3-hydroxy-2-oxoindolin-3-yl) acetic acid 3- O-6'-galactopyranosyl-2″-(2″oxoindolin-3″yl) acetate and 3-( O-β-d-glycosyl) dioxindole-3-acetic acid in Cimiciato-infected hazelnuts exhibiting a bitter off-taste. Quantitative LC-MS/MS studies, followed by dose/activity considerations confirmed for the first time asadanin to be the key contributor to the bitter taste of Cimiciato-infected hazelnuts. Furthermore, quantitative studies demonstrated that neither the physical damage alone nor a general microbial infection is able to initiate a stress-induced asadanin generation, but most likely either specific Cimiciato-specific microorganisms associated with the bugs or specific chemical stimulants in the bugs' saliva is the cause triggering asadanin biosynthesis. Finally, also germination was found for the first time to activate diarylheptanoid biosynthesis, resulting in higher contents of bitter tasting phytochemicals and development of the bitter off-taste.
Curcumin and curcuminoids have been discussed frequently due to their promising functional groups (such as scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and ...β'-hydroxy-α,β-unsaturated ketone connected with aromatic rings on both sides) that play an important role in various bioactivities, including antioxidant, anti-inflammatory, anti-proliferation and anticancer activity. A series of novel curcuminoid derivatives (a total of 55 new compounds) and three reference compounds were synthesized with good yields using three-step organic synthesis. The anti-proliferative activities of curcumin derivatives were examined for six human cancer cell lines: HeLaS3, KBvin, MCF-7, HepG2, NCI-H460 and NCI-H460/MX20. Compared to the IC
values of all the synthesized derivatives, most α,β-unsaturated ketones displayed potent anti-proliferative effects against all six human cancer cell lines, whereas β'-hydroxy-α,β-unsaturated ketones and α,β-unsaturated β-diketones presented moderate anti-proliferative effects. Two potent curcuminoid derivatives were found among all the novel derivatives and reference compounds: (
)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound
) and (1
,4
)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound
). These were selected for further analysis after the evaluation of their anti-proliferative effects against all human cancer cell lines. The results of apoptosis assays revealed that the number of dead cells was increased in early apoptosis and late apoptosis, while cell proliferation was also decreased after applying various concentrations of (
)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound
) and (1
,4
)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound
) to MCF-7 and HpeG2 cancer cells. Analysis of the gene expression arrays showed that three genes (GADD45B, SESN2 and BBC3) were correlated with the p53 pathway. From the quantitative PCR analysis, it was seen that (1
,4
)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound
) effectively induced the up-regulated expression of GADD45B, leading to the suppression of MCF-7 cancer cell formation and cell death. Molecular docking analysis was used to predict and sketch the interactions of the GADD45B-α,β-unsaturated ketone complex for help in drug design.
Estrogen receptor α (ER α) is an important therapeutic target in the regulation of ligand dependent signaling in breast cancer. The current study investigates the anti-estrogenic potential of the ...Diarylheptanoid, 5-hydroxy-7-(4-hydroxy-3 methoxyphenyl)-1-phenyl-3-heptanone (DAH) in silico. Rigid Docking analysis of DAH at the ligand binding domain (LBD) of ER α showed hydrogen bond interactions with Arg394 and Glu353 at the active site, similar to the positive controls 4-Hydroxy Tamoxifen (4-OHT) and Fulvestrant (FUL). The protein and the protein-DAH complexes were further analyzed using molecular dynamics simulations for a time scale of 50 ns using GROMACS. Root mean square fluctuation (RMSF) analysis showed large fluctuations at the N-terminal region of Helices (H) 3, 9 and at the C-terminal region of H11, which could be involved in the antagonistic conformational change. Interestingly, H12 appeared to move away from the ligand binding pocket and occupy the co-activator binding groove at the LBD of ER α. Secondary structure analysis of the protein upon binding of DAH and CUR showed structural change from α-helix to Turn conformation at H4. We hypothesize that this structural change at H4, similar to the positive control, could hinder the activity of AF-2 by blocking the binding of co-activator. These conformational changes in ER α indicate an anti-estrogenic and therapeutic potential of the DAH.
Neurodegenerative diseases represent a set of pathologies characterized by an irreversible and progressive, and a loss of neuronal cells in specific areas of the brain. Oxidative phosphorylation is a ...source of energy production by which many cells, such as the neuronal cells, meet their energy needs. Dysregulations of oxidative phosphorylation induce oxidative stress, which plays a key role in the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). To date, for most neurodegenerative diseases, there are no resolute treatments, but only interventions capable of alleviating the symptoms or slowing the course of the disease. Therefore, effective neuroprotection strategies are needed. In recent years, natural products, such as curcuminoids, have been intensively explored and studied for their therapeutic potentials in several neurodegenerative diseases. Curcuminoids are, nutraceutical compouns, that owen several therapeutic properties such as anti-oxidant, anti-inflammatory and neuroprotective effects. In this context, the aim of this review was to provide an overview of preclinical and clinical evidence aimed to illustrate the antioxidant effects of curcuminoids in neurodegenerative diseases. Promising results from preclinical studies encourage the use of curcuminoids for neurodegeneration prevention and treatment.
Aims
The aim of this study was to investigate the antimicrobial activities of Etlingera pubescens, and to isolate and identify the antimicrobial compound.
Methods and Results
The crude extracts of E. ...pubescens were obtained through methanol extraction, and evaluated for antimicrobial activities. From this extract, 1,7‐bis(3,4‐dihydroxyphenyl)heptan‐3‐yl acetate (etlingerin) was isolated. When compared to curcumin (a compound with a similar chemical structure), etlingerin showed twofold lower minimum inhibitory concentration values while also being bactericidal. Through time kill assay, etlingerin showed rapid killing effects (as fast as 60 min) against the Gram‐positive bacteria (Staphylococcus aureus ATCC 43300 and Bacillus subtilis ATCC 8188). Further assessment revealed that etlingerin caused leakage of intracellular materials, therefore suggesting alteration in membrane permeability as its antimicrobial mechanism. Cytotoxicity study demonstrated that etlingerin exhibited approximately 5‐ to 12‐fold higher IC50 values against several cell lines, as compared to curcumin.
Conclusions
Etlingerin isolated from E. pubescens showed better antibacterial and cytotoxic activities when compared to curcumin. Etlingerin could be safe for human use, though further cytotoxicity study using animal models is needed.
Significance and Impact of the Study
Etlingerin has a potential to be used in treating bacterial infections due to its good antimicrobial activity, while having potentially low cytotoxicity.
Diarylheptanoids are secondary metabolites of plants that comprise a C6–C7–C6 scaffold. They can be broadly classified into linear-type and cyclic-type diarylheptanoids based on their chemical ...structures. Actinorhizal trees, such as Casuarina, Alnus, and Myrica, which form nodule symbiosis with actinomycetes Frankia, produce cyclic diarylheptanoids (CDHs); in Alnus sieboldiana Matsum. in particular, we have reported that the addition of CDHs leads to an increase in the number of nodules. However, the information available on the biosynthesis of CDHs is scarce. A greater number of plants CDHs (including those isolated from actinorhizal trees) with a saturated heptane chain have been isolated compared with linear, non-cyclic diarylheptanoids. To identify the genes involved in the synthesis of these compounds, genes with significant sequence similarity to existing plant double-bond reductases were screened in A. sieboldiana. This report describes the isolation and characterization of two A. sieboldiana double-bond reductases (AsDBR1 and AsDBR2) that catalyze the NADPH-dependent reduction of bisdemethoxycurcumin and curcumin. The optimum pH for the two enzymes was 5.0. The apparent Km values for bisdemethoxycurcumin and NADPH were 4.24 and 3.53 μM in the case of AsDBR1, and 2.55 and 2.13 μM for AsDBR2. The kcat value was 9.4-fold higher for AsDBR1 vs. AsDBR2 when using the bisdemethoxycurcumin substrate. Interestingly, the two AsDBRs failed to reduce the phenylpropanoid monomer.
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•Two double-bond reductases (AsDBR1 and AsDBR2) were isolated from Alnus sieboldiana.•Two reductases recognized α,β-unsaturated diarylheptanoids as specific substrates.•There was a 9.4-fold difference in turnover number (kcat) between the two reductases.•AsDBRs are the first diarylheptanoid C–C double-bond reductases reported in plants.
Five undescribed monoterpene-chalcone conjugates (1-5), one undescribed hypothetical precursor of diarylheptanoid (6), two undescribed diarylheptanoids (7–8), and fourteen known compounds (9–22) were ...isolated from the seeds of Alpinia katsumadai. Their structures were elucidated through the interpretation of HRESIMS, NMR, ECD, and X-ray diffraction data. MTT assays on human cancer cell lines (HepG2, A549, SGC7901, and SW480) revealed that compounds 3–8, 11, and 13 exhibited broad-spectrum antiproliferative activities with IC50 values ranging from 3.59 to 21.78 μM. B cell lymphoma 2 was predicted as the target of sumadain C (11) by network pharmacology and verified by homogeneous time-resolved fluorescence assay and molecular docking.
Eight un\described compounds were isolated from the seeds of Alpinia katsumadai. BCL-2 was predicted as the possible target of compound 11 against HepG2 by network pharmacology and tentatively verified by HTRF assay and molecular docking. Display omitted
•Eight undescribed compounds were isolated from the seeds of Alpinia katsumadai.•Sumadain C (11) exhibited the most potent cytotoxicity against HepG2.•BCL-2 was tentatively verified as the target of sumadain C against HepG2.•Biosynthetic routes of the main compounds isolated herein were proposed.
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•Thirteen new 2,6-epoxydiarylheptanoids were isolated from A. tsao-ko.•Eight diarylheptanoids showed obvious α-glucosidase inhibitory activity.•Compounds 12 and 13 were noncompetitive ...inhibitors of α-glucosidase.•The Ki values of compounds 12 and 13 on α-glucosidase were 539.6 and 385.2 μM.
The dried fruits of Amomum tsao-ko are well-known dietary spices and traditional Chinese medicines. The random screen revealed that 50% ethanol-water extract of A. tsao-ko demonstrated significant α-glucosidase inhibitory activity with an IC50 value of 38.6 μg/mL. Bioactivity-guided isolation on the active fraction afforded 13 new 2,6-epoxy diarylheptanoids, tsaokopyranols A–M (1–13), and four known ones (14–17). Their structures featuring a 2,6-epoxy pyran ring were established by extensively spectroscopic analyses (HRESIMS, IR, UV, 1D and 2D NMR) and ECD calculations. Seven new (4–6, 8–11) and one known (16) compounds showed obvious α-glucosidase inhibitory activity with IC50 values ranging from 59.4 to 116.5 μM, higher than acarbose (IC50: 219.0 μM). An enzyme kinetic analysis indicated that compounds 12 and 13 were noncompetitive-type inhibitors of α-glucosidase with Ki values of 539.6 and 385.2 μM. This result provided new insights for the usage of A. tsao-ko, and 2,6-epoxydiarylheptanoids as new anti-diabetic candidates.
A procedure is described to measure curcumin (C), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumim (TC) and their glucuronidated metabolites (CG, DMCG, and BDMCG) in plasma, ...brain, liver and tumor samples. The procedure involves converting the analytes to their boron difluoride derivatives and analyzing them by combined liquid chromatography coupled to an ion trap mass spectrometer operating in the negative ion MSn scan mode. The method has superb limits of detection of 0.01 nM for all curcuminoids and 0.5 nM for TC and the glucuroniated metabolites, and several representative chromatograms of biological samples containing these analytes are provided. In addition, the pharmacokinetic profile of these compounds in one human who daily consumed an over-the-counter curcuminoid product shows the peak and changes in circulating concentrations achieved by this mode of administration.
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•Conversion of curcuminoids into BF2-curcuminoid complexes can be achieved in a simple one-step reaction, optimized for LC-MS analysis.•BF2-curcuminoid complexes yield an average of 28 fold increase in sensitivity on the negative ESI analysis.•The improved sensitivity of the assay enabled quantitation of these compounds in small amounts of soft tissues.•We demonstrate the application of our assay by analyzing human plasma and various soft tissues from mice.
Alnustone, a nonphenolic diarylheptanoid, first isolated from
(Betulaceae), has recently received a great deal of attention due to its various beneficial pharmacological effects. However, its ...pharmacokinetic profile in vivo remains unclear. The purpose of this study is to establish a fast and sensitive quantification method of alnustone using liquid chromatography tandem mass spectrometry (LC-MS/MS) and evaluate the pharmacokinetic and tissue distribution profiles of alnustone in rats. The sample was precipitated with acetonitrile with 0.5% formic acid and separated on BEH C
Column. The mobile phase was composed of 0.1% formic acid in water and methanol at a flow rate of 0.3 mL/min. Alnustone and the internal standard (caffeine) were quantitatively monitored with precursor-to-product ion transitions of
/
262.9→105.2 and m/z 195.2→138.0, respectively. The calibration curve for alnustone was linear from 1 to 2000 ng/mL. The intra- and inter-day assay precision (
) ranged from 1.1-9.0 % to 3.3-8.6%, respectively and the intra- and inter-day assay accuracy (
) was between -8.2-9.7% and -10.3-9.9%, respectively. The validated method was successfully applied to the pharmacokinetic studies of alnustone in rats. After single-dose intravenous administration of alnustone (5 mg/kg), the mean peak plasma concentration (C
) value was 7066.36 ± 820.62 ng/mL, and the mean area under the concentration-time curve (AUC
) value was 6009.79 ± 567.30 ng/mL∙h. Our results demonstrated that the residence time of alnustone in vivo was not long and it eliminated quickly from the rat plasma. Meanwhile, the drug is mainly distributed in tissues with large blood flow, and the lung and liver might be the target organs for alnustone efficacy. The study will provide information for further application of alnustone.
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