Minor secoiridoid aglycones from the low-polarity part of the traditional Chinese herb: Swertia mileensis

Eleven new secoiridoid aglycones involving unusual C9-skeleton:swerimilegenins A-F(1-6);bis-C9-skeleton:swerimilegenin G(7);and C_(10)-skeleton:swerimilegenins H−K(8−11),as well as six known ones,were isolated from the low-polarity part of the traditional Chinese herb medicine Swertia mileensis.Their structures were determined by extensive spectroscopic data and X-ray diffraction.Biogenetically,swerimilegenin A(1)belonged to 10-nor-secoiridoid,and swerimilegenins B-F(2-6)were 1-nor-secoiridoids.Erythrocentaurin(12)and gentiogenal(15)showed moderate anti-HBV activity on HepG 2.2.15 cell line in vitro.

The Progress of Anti-HBV Constituents from Medicinal Plants in China

Hepatitis B virus(HBV)infection causing acute and chronic hepatitis is a serious problem worldwide,whereas the current treatment methods are unsatisfactory.Traditional Chinese herbs that have long been used for medicinal purposes are fascinating sources for novel anti-HBV candidates.This paper summarizes the progress of anti-HBV constituents from diverse medicinal plants in China to provide information for searching new anti-HBV drugs from natural sources.

Chemical Constituents from Mentha haplocalyx Briq.(Mentha canadensis L.)and Theirα‑Glucosidase Inhibitory Activities

Mentha haplocalyx(Mentha canadensis)is widely used as a medicinal plant in traditional Chinese medicine,and the extracts of its aerial parts are found to signifcantly inhibit the activity ofα-glucosidase with an IC_(50) value of 21.0μg/mL.Bioactivity-guided isolation of the extracts aforded two new compounds(1 and 2),together with 23 known ones(3-25).Their structures were established by extensive spectroscopic analyses(1D and 2D NMR,MS,IR and UV).Compounds 1-17 and 21-25 were evaluated for theirα-glucosidase inhibitory activities.Compound 11 was the most active ones with an IC_(50) values of 83.4μM.These results verify theα-glucosidase inhibitory activity of M.haplocalyx(M.canadensis)and specify its active compounds for the frst time.

Anti‑oral Microbial Flavanes from Broussonetia papyrifera Under the Guidance of Bioassay

A new favane,bropapyriferol(1),and eleven known ones were isolated from the EtOAc part of Broussonetia papyrifera under the guidance of bioassay.The structure of compound 1 was determined by extensive 1D and 2D NMR,[α]_(D) spectroscopic data and quantum computation.Daphnegiravan F(2)and 5,7,3′,4′-tetrahydroxy-3-methoxy-8,5′-diprenylfavone(3)showed signifcantly anti-oral microbial activity against fve Gram-positive strains and three Gram-negative strains in vitro.Especially,compound 3 was more potent in suppressing Actinomyces naeslundii and Porphyromonas gingivalis(MIC=1.95 ppm)than the positive control,triclosan.

Artemyrianins A-G from Artemisia myriantha and Their Cytotoxicity Against HepG2 Cells

Four new sesquiterpenoids,artemyrianins A-D(1-4),and three new norlignans,artemyrianins E-G(5-7),together with five known compounds(8-12),were isolated from the aerial parts of Artemisia myriantha(Asteraceae).The new compounds were established by spectroscopic data analyses(HRMS,IR,1D and 2D NMR),and their absolute configurations were confirmed by the single-crystal X-ray diffraction or ECD calculations.The isolates showed cytotoxicity against HepG2 cells with IC50 values ranging from 33.3 to 145.2μM.

Anti-hepatitis B virus active secoiridoids from Swertia kouitchensis

Three new secoiridoids, swertiakoulactone (1) and swertiakosides A and B (2 and 3), were isolated from Swertia kouitchensis. Their structures were elucidated by comprehensive spectroscopic analyses including MS, IR, 1D and 2D NMR data. By the anti-hepatitis B virus (HBV) assay on Hep G 2.2.15 cells line in vitro, compound 1 showed moderate activities inhibiting the HBsAg secretion (IC50 = 1.10 mM, SI = 4.39) and HBV DNA replication (IC50 = 1.16 mM, SI = 4.12).

UFLC‑PDA‑MS/MS Profling of Seven Uncaria Species Integrated with Melatonin/5‑Hydroxytryptamine Receptors Agonistic Assay

Uncariae Ramulus Cum Uncis(Gou-Teng),the dried hook-bearing stems of several Uncaria plants(Rubiaceae),is a wellknown herbal medicine in China.The clinical application of Gou-Teng is bewildered for the morphological and chemical similarity between diferent species.In order to discern their chemical and biological diference,an ultra-fast liquid chromatography equipped with ion trap time-of-fight mass spectrometry(UFLC-IT/TOF-MS)combining with melatonin(MT1 and MT2)and 5-hydroxytryptamine(5-HT1A and 5-HT2C)receptors agonistic assay in vitro was conducted on seven Uncaria species.As a result,57 compounds including 35 indole alkaloids,ten favonoids,fve triterpenoids,fve chlorogenic analogues,and two other compounds were characterized based on their MS/MS patterns and UV absorptions.Specifcally,cadambine-type and corynanthein-type alkaloids were exclusively present in U.rhynchophylla and U.scandens,whereas corynoxine-type alkaloids were commonly detected in all the seven Uncaria plants.Three Uncaria species,U.rhynchophylla,U.macrophylla,and U.yunnanensis showed obviously agnostic activity on four neurotransmitter receptors(MT1,MT2,5-HT1A,and 5-HT_(2C)).This frst-time UFLCMS-IT-TOF analyses integrated with biological assay on seven Uncaria plants will provide scientifc viewpoints for the clinical application of Gou-Teng.

Artemlavanins A and B from Artemisia lavandulaefolia and Their Cytotoxicity Against Hepatic Stellate Cell Line LX2

Two new sesquiterpenoids,artemlavanins A(1)and B(3),together with fifteen known compounds(2 and 4−17)were iso-lated from the EtOH extract of Artemisia lavandulaefolia.The structures of new compounds were elucidated by extensive spectroscopic analyses(HRESIMS,1D and 2D NMR)and ECD calculations.Compound 1 was a sesquiterpenoid lactone possessing a rearranged eudesmane skeleton;compounds 2-5,6-8,9 and 10-12 belonged to the eudesmane,guaiane,oppositane and farnesane sesquiterpenoids,respectively;compounds 13-17 were the phenyl derivatives with a 4-hydroxy-acetophenone moiety.Twelve compounds(1-3,5-7,10-12,14,15 and 17)displayed cytotoxicity against hepatic stellate cell line LX2(HSC-LX2)with IC50 values ranging from 35.1 to 370.3μM.Compounds 2,7,10-12 and 17 exhibited the stronger cytotoxicity than silybin(IC50,169.6μM)with IC50 values of 82.1,35.1,95.0,83.8,81.6 and 90.1μM.Compound 7 as the most active one showed significant inhibition on the deposition of human collagen type I(Col I),human hyaluronic acid(HA)and human laminin(HL)with IC50 values of 10.7,24.5 and 13.3μM.

A Fragmentation Study on Four Unusual Secoiridoid Trimers,Swerilactones H–K,by Electrospray Tandem Mass Spectrometry

Swerilactones H–K(1–4)as four unprecedented secoiridoid trimers represent a new type of natural product,which has attracted much interest of natural chemists due to their novel skeletons and promising bioactivity.In order to well understand their MS fragmentation behaviors,they were investigated by electrospray ionization ion-trap time-of-flight multistage product ion mass spectrometry(ESI-IT-TOF-MSn)for the first time.The protonated molecules([M?H]?)of swerilactones J and K,and deprotonated molecules([M-H]-)of swerilactones H,J and K were readily observed in the conventional single-stage mass spectra(MS);however only the[M?Cl]-ion for swerilactone I was obtained in negative mode.Based on the MSn study,the fragmentation pathways of swerilactones H and I in negative mode,and swerilactones J and K in both positive and negative modes were proposed.The neutral losses of H_(2)O,CO,CO_(2)and C_(2)H_(4)O moieties are the particular elimination from the precursor ions due to the presence of hydroxyl,d-lactone and 1-O-ethyl moieties in their structures,of which the retro-Diels–Alder cleavage was the most particular dissociation.The fragment ions at m/z 341 and 291 in negative mode can be considered as the diagnostic ions for secoiridoid trimers.This investigation will provide valuable information for their fast characterization from complicated natural mixtures and extensive understanding their structural architectures.

Six New 3,5-Dimethylcoumarins from Chelonopsis praecox,Chelonopsis odontochila and Chelonopsis pseudobracteata

Ten 3,5-dimethylcoumarins(1-6 and 8‒11)involving six new ones(1-6),together with a known 3-methylcoumarin(7),were isolated from the aerial parts of three Chelonopsis plants,C.praecox,C.odontochila,and C.pseudobracteata.The struc-tures of the new compounds were determined by extensive HRESIMS,1D and 2D NMR spectroscopic analyses.According to the substitution at C-5,these coumarins were classified into 5-methyl,5-hydroxymethyl,5-formyl,and 5-nor types.All the isolates were assayed for their inhibition onα-glucosidase,protein tyrosine phosphatase 1B,and T-cell protein tyrosine phosphatase in vitro.

Synthesis and Cytotoxicity Evaluation of Tropinone Derivatives

Sixteen tropinone derivatives were prepared,and their antitumor activities against five human cancer cells(HL-60,A-549,SMMC-7721,MCF-7 and SW480)were evaluated with MTS[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium]assay.Most of the derivatives exhibited better activities compared with tropinone at the concentration of 40 pM.Particularly,derivative 6 showed significant activities with IC50 values of 3.39,13.59,6.65,13.09 and 12.38 pM respectively against HL-60,A-549,SMMC-7721,MCF-7 and SW480 cells,which suggested more potent activities than that of cis-dichlorodiamineplatinum(DDP).

Panaxadiol and Panaxatriol Derivatives as Anti-Hepatitis B Virus Inhibitors

28 Derivatives of panaxadiol(PD)and panaxatriol were synthesized and evaluated for their anti-HBV activity on HepG 2.2.15 cells,of which 17 derivatives inhibited HBV DNA replication.Compounds 4,9,10,14,and 15 showed moderate activity against HBV DNA replication with IC50 values ranged from 7.27 to 28.21 lM compared with PD.In particular,3-O-20-thenoyl panaxadiol(4)inhibited not only HBV DNA replication(IC50=16.5 lM,SI[115.7)but also HBsAg(IC50=30.8 lM,SI[62.0)and HBeAg(IC50=18.2 lM,SI[105.14)secretions.Their structure–activity relationships were discussed for guiding future research toward the discovery of new anti-HBV agents.

Triterpenoids from Uncaria rhynchophylla and Their PTP1B Inhibitory Activity

Uncaria rhynchophylla(Gouteng)is a famous traditional Chinese medicine used for psychiatric and hypotensive purposes in China.In this study,the ethyl acetate(EtOAc)part of U.rhynchophylla was revealed with protein tyrosine phosphatase 1B(PTP1B)inhibitory activity.Subsequent investigation on the EtOAc part yielded one new triterpenoid,3β-formyloxy-6β,19α-dihydroxyurs-12-en-28-oic acid(1)and four known ones,3β,6β,19α-trihydroxyurs-12-en-28-oic acid(2),2-oxopomolic acid(3),3β,19α-dihydroxy-6-oxo-olean-12-en-28-oic acid(4)and sumaresinolic acid(5).The structure of compound 1 was determined by extensive HRESIMS,IR,1D and 2D NMR spectroscopic analyses.Two ursane-type triterpenoids(2 and 3)showed selective inhibition on PTP1B with IC50 values of 48.2 and 178.7μM.The enzyme kinetic study suggested that compounds 2 and 3 were mixtype inhibitors on PTP1B with Ki values of 15.6 and 132.5μM.This investigation manifests the antidiabetic potency of U.rhynchophylla with triterpenoids as the active constituents.

Artemyrianosins A-J,cytotoxic germacrane-type sesquiterpene lactones from Artemisia myriantha

Ten new germacrane-type sesquiterpenoids,artemyrianosins A-J(1-10),were isolated from the aerial parts of Arte-misia myriantha.Their structures were elucidated by spectral analyses including UV,IR,HRESIMS,1D and 2D NMR,ECD and the absolute configurations of compounds 1 and 7-9 were characterized using X-ray crystallography.All isolates were tested their cytotoxicity against three human hepatoma cell lines(HepG2,Huh7,and SK-Hep-1),and com-pounds 1-3,7,and 10 showed cytotoxicity with IC50 values ranging from 43.7 to 89.3μM.Among them,the most active compound 3 exhibited activity against three human hepatoma cell lines with IC50 values of 43.7μM(HepG2),47.9μM(Huh7),and 44.9μM(SK-Hep-1).

Guaiane-type Sesquiterpenoid Dimers from Artemisia zhongdianensis and Antihepatoma Carcinoma Activity via the p38MAPK Pathway

17 new guaiane-type sesquiterpenoid dimers(GSDs),artemzhongdianolides B1—B17(1—17),were isolated from Artemisia zhongdianensis under the guidance of bioassay,and elucidated by spectral analyses(HRESIMS,1D and 2D NMR,IR,ECD).The absolute configuration of compounds 1,3,7,9,10,and 13 was determined by single-crystal X-ray diffraction analyses.Structurally,artemzhongdianolides B1(1)and B2(2)were the first example of the GSDs fused via a C-13/C-13'single bond,and artemzhongdianolides B3—B17 were[4+2]Diels–Alder adducts of two monomeric guaianolides.Most of the compounds showed antihepatoma cytotoxicity with IC_(50) values ranging from 9.9 to 170.1μmol/L.Importantly,artemzhongdianolide B9(9)was the most active one against three hepatoma cell lines with IC_(50) values of 13.1μmol/L(HepG2),19.5μmol/L(Huh7),and 19.5μmol/L(SK-Hep-1),and dose-dependently inhibited cell migration and invasion,induced G1 cell cycle arrest and cell apoptosis in HepG2 cells.Compound 9 might suppress HepG2 cells via affecting the p38MAPK signaling pathway suggested by machine learning approach,and significantly upregulated expression of phosphorylated p38 validated by Western blot assay.

Artemiprincepsolides A-F,Novel Germacrane-guaiane and Eudesmane-guaiane Sesquiterpenoid Dimers from Artemisia princeps and Their Antihepatoma Activity

Artemiprincepsolides A-F(1-6)were isolated from Artemisia princeps guided by bioactivity and elucidated by comprehensive spectral data and ECD calculation.Compounds 1-3 represented the first connecting model of germacrane-guaiane hetero-dimeric adducts,and compounds 4-6 were eudesmane-guaiane hetero-coupled sesquiterpenoid dimers,meanwhile,all these were presumably formed by Diels-Alder cycloaddition.Compounds 1-6 were evaluated for their hepatomatic cytotoxicity on three hepatoma cell lines,and demonstrated cytotoxicity with IC_(50)values in the range of 5.0-67.3μmol/L.Interestingly,compound 1 manifested significant cytotoxicity against HepG2,Huh7,and SK-Hep-1 cells with IC_(50)values of 9.9,9.2,and 5.0μmol/L,which were almost equivalent to the positive control,sorafenib.Flow cytometry data and Western blot assays revealed the most active compound 1 dose-dependently inhibited cell migration and invasion,and significantly induced HepG2 cells arrest in G2/M phase by downregulating proteins pcdc2 and upregulating the level of protein CyclinB1;and induced apoptosis by downregulating of Bcl-2 expression and upregulating Bax level.

Diarylheptanoid-flavanone Hybrids as Multiple-target Antidiabetic Agents from Alpinia katsumadai

The EtOAc fraction of Alpinia katsumadai seeds showed significant inhibition on glycogen phosphorylase a(GPa)with inhibitory ratios of 97.9%and 64.6%at concentrations of 200 and 100μg/mL,respectively.Bioactivity-guided isolation afforded 15 new diarylheptanoid-flavanone hybrids,katsumadainols B_(1)-B_(15)(1-15),together with eight known ones(16-23).Compounds 4-10 and 12-21 exhibited activity against GPa with IC_(50) values of 10.1-95.4μmol/L;compounds 4,5,16,and 17 displayed inhibitory effects onα-glucosidase with IC_(50) values of 7.1,12.4,7.2,and 8.3μmol/L,obviously higher than acarbose(IC_(50),209.1μmol/L);compounds 4-6,14,16-20,22,and 23 were PTP1B/TCPTP selective inhibitors with IC_(50) values of 40.7-95.8μmol/L;compounds 4,5,16,and 17 showed DPP4 inhibitory effects with inhibitory ratios of 50.0%-54.2%(200μmol/L).Diarylheptanoid-flavanone hybrids(4,5,16,and 17)with a p-hydroxybenzyl at C-6 position represent a promising class of multiple-target antidiabetic agents inhibiting GPa,α-glucosidase,PTP1B,and DPP4.

Artematrovirenolides A—D and Artematrolides S—Z,Sesquiterpenoid Dimers with Cytotoxicity against Three Hepatoma Cell Lines from Artemisia atrovirens

Inspired by the intriguing structures and remarkable activities of sesquiterpenoid dimers,12 new sesquiterpenoid dimers,artematrovirenolides A—D(1—4)and artematrolides S—Z(8—12),were isolated from the EtOAc fraction of Artemisia atrovirens through a bioactivity-guided approach.Their structures were elucidated by comprehensive spectroscopic data and absolute configuration was assigned based on single crystal X-ray diffraction data and ECD calculations.Structurally,all compounds are presumably formed via[4+2]cycloaddition involving three connecting model.Compounds 1—4 are four novel hetero-dimeric[4+2]Diels-Alder adducts dimerized from a rotundane-type unit and a guaiane-type monomer,and compounds 5—12 are eight new homo-dimeric[4+2]adducts derived from two guaianolide moieties.A putative biosynthetic pathway for compounds 1—4 was also proposed.Compounds 4,6,7,and 10 demonstrated moderate cytotoxicity against HepG2,SMMC-7721,and Huh7 cell lines with IC50 values ranging from 9.3 to 62.3μmol/L.Interestingly,compounds 5 and 11 manifested cytotoxicity with IC50 values of 13.6 and 12.8(HepG2),18.5 and 13.1(SMMC-7721),and 16.5 and 19.4μmol/L(Huh7),respectively,which were equivalent to the positive control,sorafenib.This investigation suggests that compounds 5 and 11 might be considered as potent antihepatoma candidates and deserve further structural modification and mechanism study.

Bishyoscyamine,one unusual dimeric tropane alkaloid from Anisodus acutangulus

One unusual dimeric tropane alkalolcl, blshyoscyamme, was ISOlated from the roots o! Amsoaus acutangulus, whose structure including the absolute stereochemistry was unambiguously determined based on extensive 1D NMR and 2D NMR, HR-ESI-MS [et]D and CD spectroscopic analyses. To our knowledge, bishyoscyamine is the first example of tropane alkaloid dimer condensed by a C-N bond.

Tsaokols A and B,unusual flavanol-monoterpenoid hybrids asα-glucosidase inhibitors from Amomum tsao-ko

Tsaokols A(1)and B(2),two complicated flavanol-monoterpenoid hybrids,were isolated from the dried fruits of Amomum tsao-ko under the guidance of LCMS and bioassay.Their structures were determined by extensive spectroscopic analyses and electronic circular dichroism(ECD)calculations.Compounds 1 and2 shared a flavanol backbone fused with 5/7 and 5/6 bicyclic monoterpenoid scaffolds,which were biogenetically condensed by Michael addition and acetalization.Compounds 1 and 2 exhibited significantα-glucosidase inhibitory activity with IC_(50)values of 18.8 and 38.6μmol/L(acarbose,IC_(50)=213μmol/L).Docking study supported the strong interactions of 1 and 2 bonding with enzyme by mainly hydrophobic and hydrogen-bond effects.Compounds 1 and 2 could be fast distinguished by the diagnostic ions at m/z 289 and 313 in negative MS^(2)experiments.