Two pairs of bioactive cyclohexene alkaloid enantiomers from the roots of Piper nigrum.

Two pairs of cyclohexene amide alkaloid enantiomers were obtained from the root of Piper nigrum. Their plane structures were established by NMR and HRESIMS spectra. The absolute configurations of 1a/1b and 2a/2b were determined by the comparison between the experimental and calculated electronic circular dichroism (ECD) spectra. All identified compounds were tested for inhibitory effects on acetylcholinesterase (AChE) in vitro. Notably, compounds 1b and 2b showed strong inhibitory effects on AChE and the interaction between proteins and compounds was discussed by molecular docking studies.

Highly Oxidized Germacranolides from Elephantopus tomentosus and the Configurational Revision of Some Previously Reported Analogues.

Highly oxidized germacranolides are mainly found in the genus Elephantopus, contain a characteristic ten-membered molecular core that is highly flexible, and exhibit potential cytotoxic properties. However, their configurations were assigned ambiguously in previous reports due to spectroscopic observation of macrocyclic systems. Herein, 17 highly oxidized germacranolides, including 12 new germacranolides (1-12), were isolated from Elephantopus tomentosus. Their structures were characterized by spectroscopic data analysis combined with X-ray crystallography and ECD calculations, and it was possible to propose configurational revisions of five previously reported analogues (13-17). Cytotoxic activities for 1-17 against two hepatocellular carcinoma cell lines (HepG2 and Hep3B) were tested, and compounds 1-10 and 13-16 generated IC50 values of 2.2-9.8 µM. Furthermore, the observed cytotoxic activity of 1 was determined as being mediated by inducing the apoptosis of HepG2 and Hep3B cells via mitochondrial dysfunction.

Coumarins from Sarcandra glabra (Thunb.) Nakai and Acetylcholinesterase Inhibiting Activity.

Nine coumarins including a pair of new enantiomers (1a/1b) and seven known compounds (2-8) were isolated from Sarcandra glabra (Thunb.) Nakai. Among them, compounds 1a and 1b were naturally occurring coumarin-phenylpropanoid conjugate enantiomers. Their structures were identified by NMR and ECD calculations. Compounds 1-8 were tested for acetylcholinesterase (AchE) inhibiting activity. The results of the enzymology experiment showed that compound 3 demonstrated obvious AchE inhibitory activity which showed the IC50 value of 1.982±0.003 µM, and the binding sites were predicted by molecular docking.

Insight into Isolation and Characterization of Phenolic Compounds from Hawthorn (Crataegus pinnatifida Bge.) with Antioxidant, Anti-Acetylcholinesterase, and Neuroprotective Activities.

Recent epidemiologic studies have demonstrated a link between the consumption of daily functional fruits rich in phenols and the prevention of disease for neurodegenerative disorders. Hawthorn products are derived from the functional fruit hawthorn, which is rich in phenols and has been used around the world for centuries. In order to explore the phenolic components in hawthorn, the investigation of the ethanol extract led to the separation of five new phenol compounds (1a/1b, 2-4), including one pair of enantiomers (1a/1b), along with seven disclosed analogs (5-11). Their structures were elucidated based on extensive spectroscopic analyses and electronic circular dichroism (ECD). The compounds (1-11) were tested for antioxidant activities by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonicacid) (ABTS), and ferric reducing antioxidant power (FRAP) methods. Apart from that, monomeric compounds 2, 4, and 6 exhibited more potent protective capabilities against H2O2 (hydrogen peroxide)-induced SH-SY5Y cells. Meanwhile, electronic analyses were performed using the highest occupied molecular orbital (HOMO), and the lowest unoccupied molecular orbital (LUMO) to analyze compounds 2, 4, and 6. Furthermore, compounds (1-11) measured acetylcholinesterase (AChE) inhibitory activities, and 2, 4, and 6 possessed greater AChE inhibitory activity than donepezil. At the same time, molecular docking was used to investigate the possible mechanism of the interaction between active compounds (2, 4, and 6) and AChE.

Expanded Application of Piper nigrum: Guided Isolation of Alkaloids with Inhibitory Activities of AChE/BuChE and Aß Aggregation.

Piper nigrum is a popular crop that can be used as seasoning or as an additive but its active ingredients also have an effect on the nervous system. Nineteen new amide alkaloids (1a/1b, 2-5, 6a/6b, 7, 8a/8b, 9, 10a/10b, 11a-11b, 12-14) were isolated from P. nigrum, guided by inhibitory activity of AChE and LC-MS/MS based on GNPS. The configurations were determined by extensive spectral analysis, Bulkiness rule, and NMR calculations. The inhibitory activities of AChE/BuChE and Aß aggregation were tested, and the results showed compounds 2, 7, and 12 had significant inhibitory activities. These components were identified in the crude fraction and their relative quantities were tested, which suggested that compound 2 was the index component in the active site from P. nigrum.

Two new iridoids and triterpenoid analogues from the leaves of Viburnum chingii and their anti-acetylcholinesterase activity.

Two undescribed split-ring iridoids (1-2) with six known triterpenes (3-8) and one steride (9) were isolated from the Viburnum chingii. Compound 2 possessed an unprecedented split-ring iridoid skeleton formed by electrocyclic reaction and split ring. The structures and absolute configurations of the new iridoids were established by NMR, HRESIMS, and ECD calculations. All the isolated compounds were tested for AChE inhibitory activity. Biologically, 1, 2, 3, 4, and 7 displayed significant AChE effects compared to the positive control donepezil, and have also been subjected to molecular docking studies.

Utilization of the By-Product of Corn: Guided Identification of Bioactive Terpenoids from Stigma Maydis (Corn Silk).

Stigma maydis (corn silk) (S. maydis) is a food-based by-product of maize and possesses great nutritional and pharmaceutical value. This study aimed to explore bioactive components from S. maydis. By the guidance of bioactivity-guided approach and Global Natural Products Social (GNPS) molecular networking, 12 terpenoids were discovered from S. maydis. The structures of 11 undescribed compounds (1-11) were determined by detailed spectroscopic analyses, single-crystal X-ray diffraction analysis, specific rotation calculations, electronic circular dichroism (ECD) calculations, and NMR calculations. The neuroprotective and acetylcholinesterase (AChE) inhibitory effects of 1-12 were examined, and most of them showed significant or moderate activities. The underlying neuroprotective mechanism of 4 and 5 was revealed by Hoechst 33258, AO-EB, and JC-1 staining assays. This work illustrated the potential of S. maydis as a prospective natural source of bioactive compounds in food and pharmaceutical industries.

HSQC-based small molecule accurate recognition technology discovery of diverse cytotoxic sesquiterpenoids from Elephantopus tomentosus L. and structural revision of molephantins A and B.

Elephantopus tomentosus L. is a perennial herb taxonomically belonging to the family Asteraceae, which has been used as a folk medicine for the treatment of hepatobiliary diseases. Sesquiterpenoids from this plant have broad biological activities, including anti-tumor, anti-inflammatory, and antibacterial effects. In this study, fifteen structurally diverse sesquiterpenoids comprised 11 germacrane-type and 4 eudesmane-type sesquiterpenoids were prioritized to isolated from Elephantopus tomentosus L. based on the HSQC-based Small Molecule Accurate Recognition Technology (SMART) strategy. Among them, ten sesquiterpenoids were previously unreported, and their structures were elucidated by spectroscopic data, computational methods, single-crystal X-ray diffraction crystallographic data or electronic circular dichroism calculations. In addition, the structures of two known sesquiterpenoids, molephantin A and B, which were reported to possess E-geometry for the Δ1(10) double bond, were revised by reanalyzing their spectroscopic and X-ray crystallographic data. Some sesquiterpenoids exhibited significant cytotoxic activities against Hep3B and HepG2 cell lines.

Chemical structures and anti-tyrosinase activity of the constituents from Elephantopus scaber L.

Four undescribed compounds including one germacrane-type sesquiterpene lactones (1), alkaloid (2) along with two neolignans (3-4) were isolated from Elephantopus scaber L. Their structures and absolute configurations were elucidated unambiguously by means of 1D and 2D NMR spectroscopic data analysis, and quantum chemical electronic circular dichroism calculations, as well as single-crystal X-ray crystallography. Their anti-tyrosinase activities have been evaluated in vitro and compound 2 exhibited significant inhibitory activity. Furthermore, molecular docking was performed to study the interaction patterns between 2 and the tyrosinase.

Chemical constituents from Daphne giraldii and their cytotoxicities and inhibitory activities against acetylcholinesterase.

Seven triterpenoids (1-7), two prenylated coumarins (8 and 9), and one diphenylpropane (10), including five previously undescribed compounds (1-3, 8, and 10), were obtained from the stem and root barks of Daphne giraldii. The structures and absolute configurations of the new triterpenoids were established by NMR, HRESIMS, ECD calculations, and single-crystal X-ray diffraction analysis. All identified compounds were tested for cytotoxicities (human tumour cell line Hep3B) and inhibitory effects on AChE in vitro. Notably, prenylated coumarins (8 and 9) exhibited moderate cytotoxic activities and 3-hydroxy-substituted triterpenoids (2 and 4) showed mild inhibitory effects on AChE. Furthermore, compounds 2 and 4 have also been subjected to molecular docking studies to investigate the inhibitory mechanism.

Novel Bisamide Alkaloids Enantiomers from Pepper Roots (Piper nigrum L.) with Acetylcholinesterase Inhibitory and Anti-Neuroinflammatory Effects.

The roots of Piper nigrum L., a seasoning for cooking various types of broths, are renowned for their high nutritional content and potential medicinal benefits. In this study, nine pairs of novel cyclohexene-type bisamide alkaloids (1a/1b-9a/9b) were isolated from the pepper roots using molecular network analysis strategies. Their structures were determined by extensive spectroscopic data, electronic circular dichroism (ECD) calculations, and X-ray diffraction analyses. Using an intermolecular Diels-Alder reaction, a strategy for the synthesis of bisamide alkaloids from different monomeric amide alkaloids was developed. Furthermore, these compounds were chirally separated for the first time, and compounds 3a and 5a/5b showed significant anti-neuroinflammation effects in the models of lipopolysaccharide(LPS)-induced BV2 microglial cells. Meanwhile, compounds 6b and 7a displayed concentration-dependent inhibitory activities against acetylcholinesterase with IC50 values of 6.05 ± 1.10 and 3.81 ± 0.10 µM, respectively. These findings confirmed that these bisamide alkaloids could be applied in functional food formulations and pharmaceutical products as well as facilitate the further development and usage of pepper roots.

High-throughput metabolomics enables metabolite biomarkers and metabolic mechanism discovery of fish in response to alkalinity stress.

High throughput mass spectrometry (MS)-based metabolomics is a popular platform for small molecule metabolites analyses that are widely used for detecting biomarkers in the research field of environmental assessment. Crucian carp (Carassius carassius, CC) is an economically and ecologically important fish in Asia. It can adapt to extremely high alkalinity, providing us with valuable material to understand the adaptation mechanism for extreme environmental stress. However, the information on the metabolite biomarkers and metabolic mechanisms of CC exposed to alkaline stress is not entirely clear. We applied high-throughput UPLC-Q-TOF/MS combined with chemometrics to identify changes in the metabolome of CC exposed to different concentrations of alkalinity for long term effects. Metabolic differences among alkalinity-treated groups were identified by multivariate statistical analysis. Further, 7 differential metabolites were found after exposure to alkaline conditions. In total, 23 metabolic pathways of these differential metabolites were significantly affected. Alkalinity exposure resulted in widespread change in metabolic profiles in the plasma with disruptions in the phenylalanine metabolism, glycine, serine and threonine metabolism, pyruvate metabolism, tyrosine metabolism, etc. The integrated pathway analysis of the associated metabolites showed that tRNA charging, l-cysteine degradation II, superpathway of methionine degradation, l-serine degradation, tyrosine biosynthesis IV, etc. appear to be the most significantly represented functional categories. Overall, this study demonstrated that metabolic changes in CC played a role in adaptation to the highly alkaline environmental stress.