Phenolic compounds obtained from the fruit of Crataegus pinnatifida with neuroprotective activities

Ten phenolic compounds(1a/1b,2–9)including a pair of enantiomers(1a/1b),along with eight analogues(2–9)were isolated from the fruit of Crataegus pinnatifida.Enantiomers 1a/1b were separated successfully by chiral chromatographic column.Their structures were established by comprehensive spectroscopic analyses,and the absolute configurations of enantiomers were determined by comparison between the experimental and calculated electronic circular dichroism(ECD)spectra.In addition,all isolates were investigated for their neuroprotective effects against H2O2–induced oxidative stress in human neuroblastoma SH-SY5Y cells.It was found that enantiomers 1a and 1b displayed significant neuroprotective activities but no enantioselectivity.In addition,compounds 3–6 showed obvious neuroprotective effects at different concentrations,while compound 8 exhibited potential neuroprotective effect at higher concentration(50μmol/L).

New norlignan enantiomers from the fruit of Crataegus pinnatifida with neuroprotective activities

(±)-Crataegusnorin A(la/1b) and B(2a/2b),two pairs of rare 8,9’-epoxy-type norlignan enantiomers featuring a y-butyrolactone ring,were isolated from the fruit of Crataegus pinnatifida.Their structures were determined via extensive spectroscopic analyses.Gauge-independent atomic orbital(GIAO) NMR chemical shift calculations,combined with the advanced statistical method DP4+were employed to establish the relative configurations of four compounds.Next,chiral separation was accomplished by chiral chromatographic column and the absolute configurations of the four compounds were unambiguously assigned by comparison between their experimental electronic circular dichroism curves with the quantum-mechanically calculated curves based on time-dependent density functional theory(TDDFT).All the isolates were evaluated fo r their neuroprotective activities against H2O2-induced cell injury in human neuroblastoma SH-SY5Y cells.The results showed that two pairs of enantiomers 1a/1b and 2a/2b displayed diff;erent effect on neuroprotective activity.Among them,compound 2a displayed the most potent neuroprotective effect Further flow cytometry analysis indicated that 2a could protect SH-SY5Y cells from oxidative damage through inhibiting cell apoptosis.

Isolation and Neuroprotective Activity of Phenolic Derivatives from the Marine-Derived Fungus Penicillium janthinellum

A new phenolic compound, 6-(2-acetyl-3,5-dihydroxybenzyl)-4-hydroxy-3-methyl-2H-pyran-2-one(1), along with other six known phenolic derivatives(2-7), were isolated from the mangrove rhizosphere fungus Penicillium janthinellum HK1-6 cultured in potato dextrose broth medium containing 30 g L^(-1) of natural sea salt. The structure of the new compound(1) was elucidated by comprehensive analysis of spectroscopic data including 1D and 2D NMR spectra. The proposed biosynthetic pathway of compound 1 was also studied in this research. Interestingly, a brominated phenolic derivative, aryl bromide(compound 8), was obtained from this fungal strain cultured in medium containing 30 g L^-1 of NaBr instead of natural sea salt. Compound 8 is proposed as a new natural product and formed through bromination of compound 7 when the fungus was cultured with NaBr. The neuroprotective effect of compound 1 on oxygen-glucose deprivation(OGD)-induced injury was investigated in rat spinal cord astrocytes. MTT assay demonstrated that compound 1 can attenuate OGD-induced cell viability loss in rat spinal cord astrocytes.

Neuroprotective activity of two active chemical constituents from Tinospora hainanensis

Objective:To determine the chemical structure of the new compound and investigate the protective effects of Tinosporaic acid A and B towards in-vitro neuro.Methods:The structures of two new compounds were established by analyzing its 1D and 2D NMR spectra as well as HRESIMS.Their neuroprotective effects with respect to the antioxidant properties were evaluated by radical scavenging tests and hydrogen peroxide-injured oxidative stress model in PC12 cell lines.Cell morphology of treated PC12 cells was observed by phase contrast microscopy.In-vitro MTT assay,lactate dehydrogenase activity assay and oxidative stress markers(intracellular ROS production,MDA level,and caspase-3 activity) were used to evaluate the protective effects against hydrogen peroxide induced cytotoxicity in PC12 cells.Results:The two new compounds,named Tinosporaic acid A and B,were isolated and identified from the stem bark of Tinospora hainanensis.Cell viability studies identified a representative concentration for each extract that was subsequently used to measure oxidative stress markers.Both extracts were able to reverse the oxidative damage caused by hydrogen peroxide,thus promoting PC12 cells survival.The concentration of Tinosporaic acid A and B were 86.34 μg/mL and 22.06 μg/mL respectively,which is neuroprotective for EC_(50).The results indicated that both of them significantly attenuated hydrogen peroxide-induced neurotoxicity.Conclusion:The two new compounds isolated from ethanol extracts of Tinospora hainanensis are the promising natural ones with neuroprotective activity and needed for further research.

Synthesis, Crystal Structure and Neuroprotective Activity of(E)-1-(4-(4-Chlorobenzyl)piperazin-1-yl)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one

The crystal structure of the new cinnamide derivative（E）-1-（4-（4-chlorobenzyl）piperazin-1-yl）-3-（benzo[d][1,3]dioxol-5-yl）prop-2-en-1-one（C（21）H（21）ClN2O3, Mr = 384.85） was determined by single-crystal X-ray diffraction method. Compound 5 crystallizes in the monoclinic system, space group P21/c with a = 11.762（2）, b = 15.279（3）, c = 11.865（2） , β = 116.57（3）°, V = 1907.1（7） 3, Z = 4, Dc = 1.340 g/cm3, F（000） = 808, μ = 0.224 mm-1, Mo Kα radiation（λ = 0.71073 ）, the final R = 0.0565 and w R = 0.1479 for 2318 observed reflections with I 〉 2σ（I）. Intramolecular C（9）–H（9A）···O（1） interactions as well as intermolecular C（16）–H（16A）···O（1） hydrogen bonds help to stabilize the crystal structure. The bioassay results indicated that the title compound displayed promising neuroprotection in vitro and in vivo, and suppressed apoptosis of glutamate-induced PC12 cells.

Hyperterpenoids A and B:Two pairs of unprecedented 6/6/4/6/6 polycyclic cyclobutane meroterpenoids with potent neuroprotective and anti-inflammatory activities from Hypericum beanii

Hyperterpenoid A(1)and B(2),two pairs of enantiomers,with an unprecedented 6/6/4/6/6 polycyclic skeleton,along with one known compoud hypermonone A(3)were isolated from Hypericum beanii.The racemate(±)-1 and(±)-2 were successfully separated into the two optically pure enantiomers(ee>99%)using a preparative HPLC system.Their absolute configurations were elucidated by extensive spectroscopic analyses and single-crystal X-ray diffraction method.The related plausible biogenetic pathways were pre sented.Compound 1-3 showed significant neuroprotective activity and potential antiinflammatory activity.The result that(+)-2 and(-)-2 presented different anti-inflammatory properties,may lead us to new discovery of structure activity relationship between racemates,enantiomers,and diastereomers,as well as further research regarding the binding of drugs to target proteins.

Rapid discovery of two unprecedented meroterpenoids from Daphne altaica Pall.using molecular networking integrated with MolNetEnhancer and Network Annotation Propagation

Under the guidance of the approach which integrates molecular networking,MolNetEnhancer and Net-work Annotation Propagation(NAP),daphnaltaicanoids A and B(1 and 2)with unprecedented 9-oxa-tetracyclo[6.6.1.0^(2,6).0^(8,13)]pentadecane and tetracyclo[5.3.0.1^(2,5).2^(4,11)]tridecane central frameworks were iso-lated from Daphne altaica Pall.,representing two types of unparalleled meroterpenoid cores.Their struc-tures were elucidated by extensive spectroscopic analysis,nuclear magnetic resonance(NMR)calcula-tions,DP4+analysis and electronic circular dichroism(ECD)calculations.The plausible biosynthetic path-ways for 1 and 2 were postulated.Biologically,2 exerted potent neuroprotective activities which were su-perior to trolox at 12.5 and 25μmol/L.Moreover,1 and 2 exhibited more noticeable acetylcholinesterase inhibitory activities than donepezil.Molecular docking simulations were performed to explore the inter-molecular interaction of compounds 1 and 2 with acetylcholinesterase.The bioactivity evaluation results highlight the prospects of 1 and 2 as a novel category of neurological agents.

Ten ring-B aromatized ergosterols from Aspergillus spectabilis

Spectasterols F−O(1−10),ten interesting ergosterols with an aromatized B ring,were obtained from Aspergillus spectabilis.Their structures and absolute configurations were determined using a combination of high-resolution electrospray ionization mass spectrometry(HR-ESI-MS),nuclear magnetic resonance(NMR)spectroscopy,single-crystal X-ray diffraction analyses,and electronic circular dichroism(ECD)calculations.Structurally,these aromatic ergosterols feature versatile side chains.Notably,compound aromatic ergosterols featured versatile side chains,and compound 4 is an unusual C23 ergosterol characterized by a shorter side chain due to oxidative cleavage between C-23 and C-24.All compounds were evaluated for their neuroprotective activities,with compound 8 showing a dose-dependent ability to reduce apoptosis and protect mitochondrial function in glutamate-induced SH-SY5Y cells.

Studies on the structure-activity relationship of caffeate derivatives as neuroprotective agents

In the present study,novel ester derivatives of CAPE were designed and synthesized as neuroprotective agents.The anti-inflammatory and antioxidant activities of these compounds were evaluated at the cellular level,while the blood-brain barrier(BBB)permeability was predicted by parallel artificial membrane permeability assay(PAMPA).The results revealed that phenolic hydroxyl groups and double bonds in the structure of CAPE had important effects on neuroprotective activities.Accordingly,a preliminary structure-activity relationship was summarized in this paper.In addition,we observed a significant improvement on BBB permeability.These results provided important references for the structural modification and optimization of CAPE in the future.

Undescribed Meroterpenoids from Hypericum japonicum with Neuroprotective Effects on H_(2)O_(2) Insult SH-SY5Y Cells Targeting Keap1-Nrf2

Unreported tautomeric/enantiomeric meroterpenoids,(±)-hyperjaponols I—K(1-3),were discovered from Hypericum japonicum.Comprehensive chemical investigations established the absolute characteristics of these stereoisomers.The TS calculation demon-strated that 1a and 2a easily occur enol-keto tautomerism with steady configurations individually.Amongst isolates,1b showed the strongest neuroprotective activity with the concentration at 25μmol/L on H_(2)O_(2) insult SH-SY5Y cells.In vitro molecular biological ex-periments manifested that 1b activated the Keap1-Nrf2-ARE pathway,leading to the promotion of Nrf2 nuclear translocation,down-regulation of the expression level of Keap1,and upregulation of the levels of Nrf2,NQO-1,and HO-1.The results of in silico simulation showed that 1b possessed good binding features with Keap1(5FNQ)via forming multiple typical hydrogen and hydrophobic bonds as well as less fluctuation of RMSD and RMSF during a natural physiological condition.

Design,Synthesis and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione Derivatives as Novel Neuroprotective Agents

A series of pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione derivatives was designed and synthesized,and their neuroprotective activity against SH-SY5Y cell injury induced by N-methyl-D-aspartic acid(NMDA)was evaluated.All the compounds showed significant neuroprotective effects,especially B16,which showed excellent performance and better activity than the positive control ifenprodil(B16:56.2%±0.6%;ifenprodil:41.0%±2.7%).Further investigation indicated that B16 could attenuate the Ca^(2+)influx induced by NMDA in SH-SY5Y cells and Western blotting also showed that B16 could attenuate the NR2B upregulation in SH-SY5Y cells induced by NMDA.The molecular docking results showed that compound B16 fitted in the binding pocket of NR2B-NMDAR well and could interact with binding sites of compounds 1 and 2 simultaneously.The ADME/Tox prediction results suggested that compound B16 had good blood-brain barrier(BBB)permeability and the zero alert of Pan Assay Interference Structures(PAINS)indicated that B16 could not elicit false-positive activities.These results strongly suggest that B16 is a promising and effective candidate neuroprotective compound,and that NR2B-NMDAR is a potential target of B16.

New di-spirocyclic labdane diterpenoids from the aerial parts of Leonurus japonicus

Phytochemical investigation on the ethanol extract of a well-known medicinal herb Leonurus japonicus,led to the separation of 18 labdane type diterpenoids(1-18).Through comprehensive spectroscopic analyses and quantum chemical calculations,these compounds were structurally characterized as six new interesting 5,5,5-di-spirocyclic ones(1-6),two new(7 and 8)and six known(13-18)interesting 6,5,5-di-spirocyclic ones,a new rare 14,15-dinor derivative(9),and three new ones incorporating a y-lactone unit(10-12).An in vitro neuroprotective assay in RSC96 cells revealed that compounds 7 and 12 exhibited neuroprotective activity in a concentration-dependent way,comparable to the reference drug N-acetylcysteine.

Arnequinol A and arnequinone A, two unique meroterpenoids from Arnebia euchroma

Arnequinol A(1),featuring an unprecedented 6/6/3 tricyclic carbon skeleton fused with a heptatomic oxo-bridge,together with arnequinone A(2)bearing a highly conjugated methyl-shifting benzogeijerene skeleton,were isolated from Arnebia euchroma.Their structures were elucidated by extensive spectro-scopic methods and quantum chemical calculations of the 13 C nuclear magnetic resonance(NMR)data and electronic circular dichroism(ECD)spectra.The plausible biosynthetic pathways for 1 and 2 were presented.In in vitro test,compound 2 showed potent neuroprotective activity against serum-deprivation induced PC12 cell damage at a concentration of 10μmol/L.

Ascyrones A-E, type B bicyclic ployprenylated acylphloroglucinol derivatives from Hypericum ascyron

Five new polycyclic polyprenylated acylphloroglucinols(1-5),ascyrones A-E,and four known compounds(6-9)were isolated from the aerial parts of Hypericum ascyron.All of the isolates containing a bicyclo[3.3.1]nonane-2,4,9-trione core and a benzoyl group,belonged to type B bicyclic polyprenylated acylphloroglucinols(BPAPs).Their structures and absolute configurations were established based on spectroscopic analyses and calculated electronic circular dichroism(ECD)data.The anti-inflammatory,neuroprotective and cytotoxicity activities of compounds 1-4 and 6-9 were evaluated.Compound 6 exhibited obvious anti-inflammatory activity in lipopolysaccharide(LPS)-induced RAW264.7 cells.Compounds 1 and 9 exhibited slight cytotoxicity against Hep3B cells.Meanwhile,compound 1 showed mild neuroprotective activity against corticosterone(CORT)-induced PC 12 cell damage at 10 μmol-L^(-1).

Isolation of chemical compositions as dietary antioxidant supplements and neuroprotectants from Chaga mushroom (Inonotus obliquus)

Excessive free radicals can cause oxidative stress (OS),which lead to neurodegenerative diseases (ND) are harmful to the human body.Therefore,it is necessary to explore dietary antioxidants and neuroprotectants from nutrient foods.Chaga mushroom (Inonotus obliquus ) has been used as an important functional food in many countries for centuries.This present study was carried out to discover active compounds from I.obliquus and investigate the in vitro antioxidant activity and neuroprotective activity.Sixteen natural products including two new isocoumarins (1 –2 ),a new 8-O -4′-neolignan (3 ),a new cyclic diarylheptanoid (4 ),and twelve known compounds (5 –16 ) were separated from I.obliquus .Their structures were elucidated by extensive spectroscopic analyses of high resolution electrospray mass spectrometry (HRESIMS),ultra violet (UV),and nuclear magnetic resonance (NMR).Among them,compounds 1 and 2 revealed remarkable antioxidant activities through the comprehensive analysis of DPPH,ABTS,and ferric reducing antioxidant power (FRAP) methods.Meanwhile,compound 1 demonstrated significant neuroprotective activity by increasing SH-SY5Y cells viability and preventing mitochondrial damage.Apart from that,electronic analyses were performed using the highest occupied molecular orbital (HOMO),and the lowest unoccupied molecular orbital (LUMO) to analyze compound 1 .These results indicated that compound 1 had a significant implication for the search of natural raw material to prevent OS and nerve damage in the field of functional foods,and the isocoumarin fragment as well as an oxygenated cis double-bond might be the active sites to play prominent parts in antioxidant and neuroprotective activities of compound 1 .