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.

Aromatic glycosides and lignans glycosides with their acetylcholinesterase inhibitory activities from the leaves of Picrasma quassioides.

In this study, eight new natural products were isolated from the leaves of Picrasma quassioides. Spectroscopic techniques were used for the elucidation of their planar structures. Their absolute configurations were elucidated on the basis of electron circular dichroism (ECD) techniques combined with the P/M helicity rule for the 2,3-dihydrobenzofuran chromophore, and saccharide hydrolysis. Cholinesterase inhibitors are often used as Alzheimer's disease inhibitors.Thus, acetylcholinesterase and butyrylcholinesterase inhibitory activity of these eight compounds were tested, and results showed that only compound 6 showed weakly acetylcholinesterase inhibitory activity. In particular, molecular docking was used to illustrate the bindings between compound 6 and the active sites of AChE.

Six undescribed guaianolide-type sesquiterpenes from the aerial parts of Daphne penicillata.

Six undescribed guaianolide sesquiterpenes (1-6) were obtained from the aerial parts of Daphne penicillata. Their structures and absolute configuration were elucidated by HRESIMS, NMR analyses, ECD calculations and single-crystal X-ray diffraction analysis. Structurally, all compounds possess the typical 5,7-fused system of 8,12-guaianolides and this guaianolide-type was first reported to be isolated from Daphne penicillata. All compounds (1-6) were evaluated for anti-inflammatory and cytotoxic activity. Among them, compounds 1 and 5 showed moderate inhibitory effects on LPS-induced NO production in BV2 cells and 4 displayed potential inhibition against Hep3B cells with an IC50 value of 7.33 µM.

Discovery of Michael reaction acceptors from the leaves of Ailanthus altissima by a modified tactic.

Structural characteristics-guided investigation of Ailanthus altissima (Mill.) Swingle resulted in the isolation and identification of seven undescribed potential Michael reaction acceptors (1-7). Ailanlactone A (1) possesses an unusual 1,7-epoxy-11,12-seco quassinoid core. Ailanterpene B (6) was a rare guaianolide-type sesquiterpene with a 5/6/6/6-fused skeleton. Their structures were determined through extensive analysis of physiochemical and spectroscopic data, quantum chemical calculations, and single crystal X-ray crystallographic technology using Cu Kα radiation. The cytotoxic activities of isolates on HepG2 and Hep3B cells were evaluated in vitro. Encouragingly, ailanaltiolide K (4) showed significant cytotoxicity against Hep3B cells with IC50 values of 1.41 ± 0.21 µM, whose covalent binding mode was uncovered in silico.

Stereochemical insights into structurally diverse lignanamides from the herbs of Solanum lyratum Thunb.

A chemical investigation of Solanum lyratum Thunb. (Solanaceae) afforded six pairs of enantiomeric lignanamides consisting of twelve undescribed compounds, along with two undescribed racemic mixtures, and the separations of the enantiomers were accomplished by chiral-phase HPLC. The structures of these undescribed compounds were elucidated by the analysis of spectroscopic data, NMR and electronic circular dichroism calculations. All isolated compounds were assessed for neuroprotective activities in H2O2-induced human neuroblastoma SH-SY5Y cells, and acetylcholinesterase (AChE) inhibitory activities. Among tested isolates, some enantiomeric lignanamides exhibited conspicuous neuroprotective effects and AChE inhibitory effect.

Four Pairs of Neuroprotective Aryldihydronaphthalene-Type Lignanamide Enantiomers from the Herbs of Solanum lyratum.

Four pairs of aryldihydronaphthalene-type lignanamide enantiomers were isolated from Solanum lyratum (Solanaceae). The enantiomeric separation was accomplished by chiral-phase HPLC, and five undescribed compounds were elucidated. Analysis by various spectroscopy and ECD calculations, the structures of undescribed compounds were illuminated. The neuroprotective effects of all compounds were evaluated using H2 O2 -induced human neuroblastoma SH-SY5Y cells and AchE inhibition activity. Among them, compound 4 a exhibited remarkable neuroprotective effects at high concentrations of 25 and 50 µmol/L comparable to Trolox. Compound 1 a showed the highest AchE inhibition with the IC50 value of 3.06±2.40 µmol/L. Molecular docking of the three active compounds was performed and the linkage between the compounds and the active site of AchE was elucidated.

Neuroprotective and acetylcholinesterase inhibitory activities of alkaloids from Solanum lyratum Thunb.: An in vitro and in silico analyses.

The n-BuOH extract from the herb of Solanum lyratum Thunb. (Solanaceae) was purified by various chromatographic methods, which led to the isolation of seven undescribed alkaloids ((-)-(7'S)-N-feruloyltyramine A, (+)-(7'R)-N-feruloyltyramine A, (+)-(7'S)-N-solanamide A, (-)-(7'R)-N-solanamide A, 7'S-perillascens, solanpyrrole A, and (Z)-asmurratetra A) and 13 known alkaloids, including four pairs of enantiomers. Extensive spectroscopic data and electronic circular dichroism (ECD) calculations were applied to determine the structures of the undescribed compounds. In in vitro biological activity assays, (-)-(7'S)-N-feruloyltyramine A and (+)-(7'R)-N-feruloyltyramine A exhibited pronounced neuroprotective effects against SH-SY5Y cell damage with survival rates of 75.98% and 76.61%, respectively, at 50 µM. Additionally, (-)-(7'S)-N-feruloyltyramine A and N-cis-feruloyl-3'-methoxy-tyramine displayed acetylcholinesterase (AChE) inhibitory effects with IC50 values of 7.41 ± 1.76 µM and 9.21 ± 0.89 µM, respectively. Molecular docking simulations revealed that (-)-(7'S)-N-feruloyltyramine A had a binding site for AChE. These findings reveal the structural diversity of the bioactive compounds in S. lyratum and provides insights into the use of this information for the production of functional components in the pharmaceutical industry.

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.

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.

Flavonoids with antioxidant and tyrosinase inhibitory activity from corn silk (Stigma maydis).

Corn silk (Stigma maydis), being the styles and stigmas of maize, is a famous traditional medicine and functional tea in China. Research into the chemical composition of corn silk led to the identification of an unreported flavone (1, silkone A), accompanying with three known flavonoids (2-4). And their structures were elucidated through comprehensive spectroscopic analysis. Each obtained compound was evaluated for antioxidant capacity by DPPH, ABTS and FRAP assays. As a result, all tested compounds exhibited stronger radicals scavenging activities than Trolox in ABTS radical assay and displayed relatively weak antioxidant capacity in the other two experiments. Tyrosinase inhibitory activities of compounds 1-4 were also investigated, and compounds 3 and 4 demonstrated moderate inhibitory activities to tyrosinase with IC50 values of 0.49 and 0.21 mM, respectively, which was further investigated through molecular docking calculation. These results may contribute to the development of novel antioxidants and tyrosinase inhibitors from corn silk.

Vibsane-type diterpenoids from Viburnum odoratissimum inhibit hepatocellular carcinoma cells via the PI3K/AKT pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with an elevated danger of metastasis and a short survival rate. Vibsane-type diterpenoids with novel structures possess marked antitumor activities against multiple cancer cells. However, the exact mechanism is poorly unclear. PURPOSE: To assess the antitumor mechanism of vibsane-type diterpenoids derived from Viburnum odoratissimum (V. odoratissimum) against HCC cells in vitro and in vivo. METHODS: The main constituents in the ethyl acetate extract of V. odoratissimum (EAVO) were identified by LC-MS/MS. The antiproliferative activity of EAVO in vitro was evaluated by MTT assays. Annexin V-FITC/PI, AO/EB, and Hoechst 33,258 staining were employed to detect apoptosis. JC-1 fluorescence dye was used to detect the mitochondrial membrane potential (MMP). The levels of intracellular ROS and mitochondrial superoxides were assessed by H2DCF-DA and MitoSox staining, respectively. The levels of oxidative stress were determined by ROS Green™ H2O2 probe, hydroxyphenyl fluorescein (HPF), and the C11 BODIPY 581/591 fluorescent probe. Transcriptomics was performed to investigate the antitumor mechanism of EAVO in HCC. The molecular mechanism by which EAVO suppressed HCC cells was verified by Western blot, RT-PCR, and HTRF® KinEASE™-STK S3 kits. The efficacy and safety of EAVO in vivo were evaluated using Hep3B xenograft models. RESULTS: Vibsane-type diterpenoids were the main constituents of EAVO by LC-MS/MS. EAVO suppressed proliferation, aggravated oxidative stress, and promoted apoptosis in HCC cells. Moreover, EAVO dramatically inhibited tumor growth in Hep3B xenograft models. Transcriptomics results indicated that EAVO inhibited HCC cell proliferation by regulating the PI3K/AKT pathway. Vibsanin B, vibsanol I, and vibsanin S isolated from EAVO was used to further verify the antitumor activity of vibsane-type diterpenoids subsequently. Interestingly, the kinase results showed that vibsanin B and vibsanol I exhibited vital AKT kinase inhibitory activities. CONCLUSIONS: Collectively, this study provided a comprehensive mechanism overview of vibsane-type diterpenoids against HCC cells in vitro and in vivo. It also laid a foundation for further antitumor investigation of vibsane-type diterpenoids in V. odoratissimum.

Solanoids F - I: Terpenoids from Solanum lyratum with neuroprotective effects against H2O2-induced SH-SY5Y cell injuries.

Four new terpenoids, solanoids F - I (1-4), together with eleven known compounds (5-15), were isolated from the whole herb of Solanum lyratum. The chemical structures were characterized by spectroscopic techniques, and electronic circular dichroism (ECD) data analysis was adopted to confirm the absolute configurations of 1-4. Compounds 1-6, 8 and 12-15 exhibited neuroprotective effects against H2O2-induced oxidative damage of human SH-SY5Y cells. Additionally, this study also combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to explore the potential targets and signaling pathways of active terpenoids components in intervening Alzheimer's disease (AD).

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.

Diverse sesquiterpenoids from Litsea lancilimba Merr. with potential neuroprotective effects against H2O2-induced SH-SY5Y cell injury.

Five undescribed sesquiterpenoids (1-5), and nine known sesquiterpenoids (6-14) were obtained from the fruits of Litsea lancilimba Merr. by LC-MS/MS molecular networking strategies. Litsemene A (1) possessed a unique 8-member ring through unexpected cyclization of the methyl group on C-10 of guaiane. Their structures were elucidated by spectroscopic techniques including IR, UV, NMR, HR-ESI-MS, and their absolute configurations were assigned by ECD calculations. All isolated sesquiterpenoids were analyzed by bioinformatics and evaluated for their neuroprotective effects against H2O2-induced injury in human neuroblastoma SH-SY5Y cells.

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.

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.

Acylated sucroses and butenolide analog from the leaves of Tripterygium wilfordii Hook. f. and their potential anti-tyrosinase effects.

Three undescribed acylated sucroses (1-3), one undescribed butenolide analog (4) along with three known compounds (5-7) were isolated from the aqueous EtOH extract of the dried leaves of Tripterygium wilfordii. Their structures were elucidated on the basis of spectroscopic analyses, electron circular dichroism (ECD) techniques, and saccharide hydrolysis. All the isolated compounds were tested for their anti-tyrosinase effects. Among them, 6 exhibited similar inhibitory effects on tyrosinase with IC50 values of 0.073 mM comparing to arbutin. Additionally, the possible mechanism of the interaction between 6 and the active site of tyrosinase was explored by molecular docking.

Lignans with neuroprotective activity from the fruits of Crataegus pinnatifida.

Seven lignans (1a/1b-2a/2b and 3-5), including six new compounds (1b, 2a/2b, 3-5), were isolated from the fruits of Crataegus pinnatifida. Their structures were elucidated by comprehensive spectroscopic analyses. Compounds 1b/1b-2a/2b were two pairs of enantiomers and the absolute configurations were determined by comparison of their experimental and calculated ECD spectra. Moreover, bioinformatics analysis suggested that more than a third of diseases were related to the nervous system. Therefore, all compounds were evaluated for neuroprotective effects toward human neuroblastoma SH-SY5Y cells injury induced by H2O2. Among them, compound 1a exhibited moderate protective effect.

Small Molecule Accurate Recognition Technology accelerated isolation of structurally diverse sesquiterpenes from Litsea lancilimba Merr.

Four undescribed sesquiterpenes (1-4) and 20 known sesquiterpenes (5-24) were obtained from the fruits of Litsea lancilimba Merr. by Small Molecule Accurate Recognition Technology (SMART). The gross structures and the relative configurations of the new compounds were deduced by spectroscopic data analysis. The absolute configurations were defined by comparison of their experimental and calculated electronic circular dichroism (ECD) spectra data. All compounds were screened for their neuroprotective effects against H2O2-induced SH-SY5Y cells injury. Compounds 2, 3, 7, 8 and 13 exhibited comparable neuroprotective activity to the positive trolox at 50 µM.

The nature compound dehydrocrenatidine exerts potent antihepatocellular carcinoma by destroying mitochondrial complexes in vitro and in vivo.

Cumulative evidence indicates that mitochondria dysfunction plays an important role in tumour treatment. Given the limited efficacy and toxicity of current mitochondria-targeted drugs, research into effective mitochondria-targeted anticancer agents remains an irresistible general trend. In this study, it was found that dehydrocrenatidine (DEC), a ß-carbolin alkaloid isolated from Picrasma quassiodes, displays a promising growth inhibitory effect in vitro and in vivo by inducing apoptosis of hepatocellular carcinoma (HCC) cells. Mechanistically, we provided that the possible target of DEC against HCC cells was determined by isobaric labels for relative and absolute quantification assay and validated them using further experiments. The results suggested that DEC can target and regulate the function of mitochondrial complexes I, III and IV, affecting oxidative phosphorylation and ultimately leading to mitochondrial dysfunction to exert its anti-HCC effects. In addition, the combination of DEC and sorafenib showed a synergistic effect and was also associated with mitochondrial dysfunction. Importantly, DEC did not show significant toxicity in mice. This study provided a new insight into underlying mechanisms in DEC-treated HCC cells, suggesting that DEC might be a mitochondrial targeting lead compound.