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Artemisia annua L. ("Qinghao" in Chinese) is a famous traditional Chinese medicinal herb and has been used to treat malaria and various tumors. Our preliminary screening indicated that the EtOAc extract of A. annua manifested activity against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 53.2%, 52.1%, and 59.6% at 200 μg/mL, respectively. Bioassay-guided isolation of A. annua afforded 14 unusual cadinane-involved sesquiterpenoid dimers, artemannuins A‒N (1-14), of which the structures were elucidated by extensive spectral analyses, ECD calculations, and single-crystal X-ray diffraction. Structurally, these compounds were classified into five different types based on the coupled modes of two monomeric sesquiterpenoids. Among them, compounds 1-9 represented the first examples of sesquiterpenoid dimers formed via the C-3‒C-3' single bond of two 5(4 → 3)-abeo-cadinane sesquiterpenoid monomers, while compounds 13 and 14 were dimers fused by cadinane and humulane sesquiterpenoids via an ester bond. Methylated derivatives of 1, 4, 6, and 8 showed antihepatoma activity against HepG2, Huh7, and SK-Hep-1 cell lines with IC 50 values ranging from 30.5 to 57.2 μM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Despite the development of an increasing number of multi-kinase and immune checkpoint inhibitors for hepatocellular carcinoma (HCC), improvement in cancer survival remains limited due to their similar structures and targets. Natural products (NPs) maintain diverse structures and activities and are important sources of drug discovery. Currently, most of active NPs exhibit ambiguous binding targets and mechanisms. Herein, we proposed the CIPHEN ( c ompound-protein i nteractions p rediction based on the he terogeneous n etwork) to predict potential antihepatoma NPs and their targets. The evaluation of canonical compound-protein interactions (CPIs) databases and independent test demonstrated the good ability of CPIHN to reveal known and unreported CPIs. Both prediction and experiment results indicated that CIPHEN could unveil relationships between actively antihepatoma sesquiterpenoid dimers (SDs) and anti-HCC targets. In conclusion, the CIPHEN provides a promising choice to investigate the mode of action of compounds, which will help to accelerate the process of drug research and development against HCC., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Artemyriantholides A-K (1-11) as well as 14 known compounds (12-25) were isolated from Artemisia myriantha var. pleiocephala (Asteraceae). The structures and absolute configuration of compounds 2 and 8-9 were confirmed by the single crystal X-ray diffraction analyses, and the others were elucidated by MS, NMR spectral data and electronic circular dichroism calculations. All compounds were chemically characterized as guaiane-type sesquiterpenoid dimers (GSDs). Compound 1 was the first example of the GSD fused via C-3/C-11' and C-5/C-13' linkages, and compounds 2 and 5 were rare GSDs containing chlorine atoms. Eleven compounds showed obvious inhibitory activity in HepG2, Huh7 and SK-Hep-1 cell lines by antihepatoma assay to provide the IC 50 values ranging from 7.9 to 67.1 μM. Importantly, compounds 5 and 8 exhibited the best inhibitory activity with IC 50 values of 14.2 and 18.8 (HepG2), 9.0 and 11.5 (Huh7), and 8.8 and 11.3 μM (SK-Hep-1), respectively. The target of compound 5 was predicted to be MAP2K2 by a computational prediction model. The interaction between compound 5 and MAP2K2 was conducted to give docking score of -9.0 kcal/mol by molecular docking and provide K D value of 43.7 μM by Surface Plasmon Resonance assay., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Guaianolide dimers represent a unique class of natural products with anticancer activities, but their low content in plants has limited in-depth pharmacological studies. Lavandiolide I is a guaianolide dimer isolated from Artemisia species, and had been synthesized on a ten-gram scale in four steps with 60 % overall yield, which showed potent antihepatoma activity on the HepG2, Huh7, and SK-Hep-1 cell lines with IC 50 values of 12.1, 18.4, and 17.6 µM, respectively. To explore more active dimers, 33 lavandiolide I derivatives were designed, synthesized, and evaluated for their inhibitory activity on human hepatoma cell lines. Among them, 10 derivatives were more active than lavandiolide I and sorafenib on the three cell lines. The primary structure-activity relationship concluded that the introduction of aldehyde, ester, azide, amide, carbamate and urea functional groups at C-14' of the guaianolide dimer significantly enhanced the antihepatoma activity. Among these compounds, derivatives 25, 27, and 33 enhanced antihepatoma activity more than 1.2-5.8 folds than that of lavandiolide I, and demonstrated low toxicity to the human liver cell lines (THLE-2) and good safety profiles with selective index ranging from 1.3 to 3.4, while lavandiolide I was more toxic to THLE-2 cells. This work provides new insights into enhancing the antihepatoma efficacy and reducing the toxicity of sesquiterpenoid dimers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The ethanol and EtOAc extracts of Artemisia sacrorum exhibited inhibitory effect against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 65.5%, 28.1%, 84.6%, and 93.5%, 82.0%, 89.0% at 200 μg/mL. Twenty-three undescribed guaiane-type sesquiterpene lactones, artemisacrolides A‒W, were isolated from A. sacrorum under the guidance of antihepatoma activity. Their structures were elucidated by spectral data (HRESIMS, IR, UV, 1D and 2D NMR), ECD calculations, and a single-crystal X-ray diffraction. Artemisacrolides A‒U were guaiane-type sesquiterpene lactones possessing α-methylene-γ-lactone and containing acetoxyl groups at C-8, and artemisacrolides V and W represented the first report from the genus Artemisia with a 1,10-rearranged guaiane-type sesquiterpene lactone. Antihepatoma assay suggested that artemisacrolides A‒U demonstrated better inhibitory activity in Huh7 and SK-Hep-1 cells than those of HepG2 cells. Among them, nine compounds exhibited significant inhibitory activity against Huh7 cells with IC 50 values of 8.2-14.3 μM, superior or equal to that of sorafenib; seven compounds demonstrated obvious activity against SK-Hep-1 cells with IC 50 values of 13.5-19.2 μM, which were equivalent to that of sorafenib. Artemisacrolides B and E were the most active ones in three human hepatoma cell lines with IC 50 values of 21.9, 8.2, 16.9 and 22.6, 9.0, 17.3 μM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Artemongolins A-K (1-11), which are undescribed sesquiterpenoid dimers, were obtained from Artemisia mongolica and characterized through comprehensive spectral data, including HRESIMS, IR, 1D and 2D NMR, and ECD calculations. The absolute configurations of compounds 1, 4, and 7 were undoubtedly determined by a single-crystal X-ray crystallography. Artemongolins A-K (1-11) featured a rare 5/7/5/5/5/10 hexacyclic system composed of a germacrene and a guaianolide by a fused 2-oxaspiro[4,4]nonane-1-one ring system. Antihepatoma evaluation against three human hepatoma cell lines demonstrated that the most active compounds 5 and 6 displayed inhibitory activity with IC 50 values of 88.6 and 57.0 (HepG2), 59.1 and 26.4 (Huh7), and 67.5 and 32.5 (SK-Hep-1) µM, respectively., (© 2023. The Pharmaceutical Society of Korea.)

Artemeriosides A-F (1-6), six novel sesquiterpenoids containing a 6'-O-crontonyl β-glucopyranoside, were isolated from Artemisia annua L. Their structures were determined by spectral data including HRESIMS, IR, UV, 1D and 2D NMR, and ECD calculations. Compounds 1-6 represented the first examples of natural sesquiterpenoid substituted by 6'-O-crontonyl β-glucopyranoside. By antihepatoma assay, compounds 1 and 2 demonstrated inhibitory effect against both HepG2 and SK-Hep-1 cells with inhibitory ratios of 77.0%, 88.8%, and 86.8%, 83.9% at 200.0 μM, and compound 1 showed inhibitory activity against Huh7 cells with inhibitory ratio of 56.8%., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

Inspired by our previous finding that disesquiterpenoids showed more potent antihepatoma cytotoxicity than their corresponding parent monomers, natural product-like guaianolide-germacranolide heterodimers were designed and synthesized from guaianolide diene and germacranolides via a biomimetic Diels-Alder reaction to provide three antihepatoma active dimers with novel scaffolds. To explore the structure-activity relationship, 31 derivatives containing ester, carbamate, ether, urea, amide, and triazole functional groups at C-14' were synthesized and evaluated for their cytotoxic activities against HepG2, Huh7, and SK-Hep-1 cell lines. Among them, 25 compounds were more potent than sorafenib against HepG2 cells, 15 compounds were stronger than sorafenib against Huh7 cells, and 17 compounds were stronger than sorafenib against SK-Hep-1 cells. Compound 23 showed the most potent cytotoxicity against three hepatoma cell lines with IC 50 values of 4.4 µM (HepG2), 3.7 µM (Huh7), and 3.1 µM (SK-Hep-1), which were 2.7-, 2.2-, and 2.8-fold more potent than sorafenib, respectively. The underlying mechanism study demonstrated that compound 23 could induce cell apoptosis, prevent cell migration and invasion, cause G2/M phase arrest in SK-Hep-1 cells. Network pharmacology analyses predicted PDGFRA was one of the potential targets of compound 23, and surface plasmon resonance (SPR) assay verified that 23 had strong affinity with PDGFRA with a dissociatin constant (KD) value of 90.2 nM. These promising findings revealed that structurally novel guaianolide-germacranolide heterodimers might provide a new inspiration for the discovery of antihepatoma agents., (© 2023 Wiley Periodicals LLC.)

Artemyrianolide H (AH) is a germacrene-type sesquiterpenolid isolated from Artemisia myriantha, and showed potent cytotoxicity against three human hepatocellular carcinoma cell lines HepG2, Huh7, and SK-Hep-1 with IC 50 values of 10.9, 7.2, and 11.9 µM, respectively. To reveal structure-activity relationship, 51 artemyrianolide H derivatives including 19 dimeric analogs were designed, synthesized, and assayed for their cytotoxicity against three human hepatoma cell lines. Among them, 34 compounds were more active than artemyrianolide H and sorafenib on the three cell lines. Especially, compound 25 exhibited the most promising activity with IC 50 values of 0.7 (HepG2), 0.6 (Huh7), and 1.3 µM (SK-Hep-1), which were 15.5, 12.0, and 9.2-fold higher than that of AH and 16.4, 16.3 and 17.5-fold higher than that of sorafenib. Cytotoxicity evaluation on normal human liver cell lines (THLE-2) demonstrated good safety profile of compound 25 with SI of 1.9 (HepG2), 2.2 (Huh 7) and 1.0 (SK-Hep1). Further studies revealed that compound 25 dose-dependently arrested cells at G2/M phase which was correlated with the up-regulation of both cyclin B1 and p-CDK1, and induced apoptosis through the activation of mitochondrial pathways in HepG2 cells. In addition, the migratory and invasive abilities in HepG2 cells after treatment with 1.5 μM of compound 25 were decreased by 89% and 86% with the increase of E-cadherin expression accompanied by the decrease of N-cadherin, vimentin expression. Bioinformatics analysis based on machine learning predicted that PDGFRA and MAP2K2 might be acting targets of compound 25, and SPR assays demonstrated compound 25 were bound with PDGFRA and MAP2K2 with K D value of 0.168 nM, and 8.49 µM, respectively. This investigation proposed that compound 25 might be considered as a promising lead compound for the development of antihepatoma candidate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The accumulation of CD4 + Foxp3 + regulatory T cells (Tregs) in the tumor microenvironment (TME) dampens anti-tumor immune responses and promotes tumor progression. Therefore, the elimination of Tregs has become a strategy to enhance the efficacy of tumor immunotherapy, although it is still a daunting challenge. Rhododendron brachypodum (R. brachypodum) is a perennial shrub mainly distributed in Southwestern China, whereas the chemical constituents in this plant remain elusive., Purpose: To identify small-molecule inhibitors of Tregs from R. brachypodum., Methods: Meroterpenoids in R. brachypodum were isolated by column chromatography under the guidance of LCMS analyses. The structures of isolates were identified by spectroscopic data and quantum calculations. The activities of compounds were first evaluated on CD4 + T cell differentiation by flow cytometry in Th1, Th2, Th17, and Treg polarizing conditions, and then on CT26 and MC38 murine colorectal carcinoma cells-allografted mice models. The mechanism of action was first investigated by determining Foxp3 degradation in Jurkat T cells transfected with pLVX-TetOne-Puro-Foxp3-tGFP, and then through analyses of Foxp3 expression on several pre-transcriptional signaling molecules., Results: Two new prenylated phenolic acids (1 and 2) and a chromane meroterpenoid, rubiginosin B (RGB, 3) were obtained from R. brachypodum. The structure of S-anthopogochromene C (1) was rectified according to the electronic circular dichroism (ECD) experiment, and rhodobrachypodic acid (2) was proposed as the precursor of RGB by photochemical transformation. In this investigation, we first found that RGB (3) selectively suppressed the de novo differentiation of TGFβ-induced CD4 + Foxp3 + regulatory T cells (iTregs), overcome the immunosuppressive TME, and consequently inhibited the growth of tumor in mouse models. The mechanistic study revealed that RGB could target calcineurin, inhibited the nuclear factor of activated T cells (NFAT) dephosphorylation, and down-regulated Foxp3 expression. The hypothetical binding modes of RGB with calcineurin were predicted by molecular docking, and the interactions were mainly hydrophobic effects and hydrogen bonds., Conclusion: These results suggest that RGB enhances anti-tumor immune responses by inhibiting Treg cell differentiation through calcineurin-NFAT signaling pathway, and therefore RGB or its analogs may be used as adjuvant agents meriting further investigation., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Artemisia annua , also known as "Qinghao" in Chinese, is a famous traditional Chinese medicine and has been used for the treatment of malaria and various tumors. In this study, three novel sesquiterpenoid-flavonol hybrids, artemannuols A-C (1-3), were isolated and elucidated by extensive spectral data and ECD calculations. Structurally, artemannuols A-C (1-3) are the first examples of sesquiterpenoid-flavonol hybrids fused by an ether bond, among which artemannuols A and B (1 and 2) are composed of bisabolane-type sesquiterpenoid and flavonol moieties, and artemannuol C (3) is composed of humulane-type sesquiterpenoid and flavonol moieties. The antihepatoma assay suggested that compounds 1-3 showed inhibitory effects against HepG2, Huh7, and SK-Hep-1 cell lines with IC 50 values in the range of 32.7 to 70.4 μM.

Bioassay-guided investigation of the active fraction of Artemisia princeps led to 13 undescribed sesquiterpenoid dimers, artemiprinolides A-M (1-13), together with 11 known ones (14-24). Their structures were elucidated by comprehensive spectroscopic data and absolute configurations were assigned based on single crystal X-ray diffraction data and ECD calculations. Structurally, all compounds were postulated to be derived from the Diels-Alder cycloaddition. The isolated dimers except 11 and 15 were assayed for their cytotoxicity against HepG2, Huh7, and SK-Hep-1 cell lines, of which four compounds (3, 13, 17, 18) exhibited obvious cytotoxicity with IC 50 values ranging from 8.8 to 20.1 μM. Interestingly, the most active compounds 1 and 16 manifested significant cytotoxicity on the three tested hepatoma cell lines with IC 50 values of 5.4, 4.1 (HepG2), 7.7, 5.6 (Huh7), and 11.8, 15.7 μM (SK-Hep-1), respectively, which were better than sorafenib. Compound 1 dose-dependently inhibited cell migration and invasion, and significantly induced the HepG2 cell arrest in G2/M phase by downregulating cdc2 and pcdc2 and upregulating cyclinB1; and induced apoptosis by downregulating Bcl-2 expression and upregulating Bax level. The molecular docking study implied that the carbonyl at the C-12' of 1 had a strong binding affinity with PRKACA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Fractionation of the ethanol extract of Artemisia verlotorum led to the identification of eight undescribed eudesmane-type sesquiterpenoids, artemverlolides A-H (1-8). Their structures were determined by spectral analyses (HRESIMS, 1D and 2D NMR, IR, and ECD). Network pharmacology predicted that compounds 1-8 might be target on AURKA, CCNA2, CYP2C19, and EPHX2 with possibly antihepatoma effect from Swiss TargetPrediction and Gene Expression Omnibus database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the targets significantly enriched in FoxO signaling pathway. The molecular docking suggested that compound 8 had high binding affinity with AURKA. Furthermore, the interaction between compound 8 and AURKA was determined by Surface Plasmon Resonance (SPR) assay. The result suggested that compound 8 bound to AURKA with KD value of 68.0μM and was consistent with the predicted data, demonstrating that AURKA might be one of acting targets of 8., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Twelve undescribed and 13 known eudesmane-type sesquiterpenoids were obtained from Artemisia leucophylla, and structurally elucidated based on comprehensive analyses of spectral data, including HRESIMS, IR, 1D and 2D NMR, and ECD calculation. The absolute configuration of compound 1 was determined by a single X-ray single crystal diffraction. Chemically, compounds 1-5 featured unprecedented 1,2-seco-1-nor-eudesmane-type skeleton with a cis-fused 6/5 bicyclic system. Antihepatoma evaluation against three human hepatoma cell lines (HepG2, Huh7, and SK-Hep-1) for all compounds demonstrated that compound 7 displayed the most active cytotoxicity with IC 50 values of 35.1, 35.0, and 32.7 μΜ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Artemongolides A-E (1-5), an unusual class of diseco-guaianolides featuring a rare fused 7-methylbicyclo[2.2.1]-2-ene-7-heptanol ring system, and artemongolide F (6), the first example of [4 + 2] Diels-Alder type adducts presumably incorporating a chain farnesane sesquiterpene and a guaianolide diene, were isolated from the whole plant of Artemisia mongolica. Their structures were elucidated based on the spectroscopic analyses of UV, IR, MS, and 1D and 2D NMR spectra. The absolute configurations of artemongolides A (1) and F (6) were determined by single-crystal X-ray crystallography, and those of artemongolides B-E (2-5) were established by ECD calculations. Cytotoxicity evaluation suggested that compound 1 exhibited activity against HSC-LX2 cells with an IC 50 value of 165.0 μM, equivalent to that of the positive control silybin (IC 50 , 146.4 μM). Preliminary mechanism studies revealed that compound 1 could inhibit the deposition of human collagen type I (Col I), human hyaluronic acid (HA), and human laminin (HL) with IC 50 values of 123.8, 160.4, and 139.20 μM.

Background: CD4 + Foxp3 + regulatory T cells (Tregs) represent the primary cellular mechanism of tumor immune evasion. Elimination of Treg activity by the pharmacological agent may enhance anti-tumor immune responses. However, Treg-eliminating agents, especially those with small molecules, are rarely reported., Purpose: To identify small molecule inhibitors of Treg cells from natural products., Methods: Compounds from Diploclisia glaucescens were isolated by column chromatography, and structures were identified by spectroscopic evidence and quantum calculations. The tet-On system for Foxp3-GFP expression in Jurkat T cells was generated to screen Treg inhibitors based on Foxp3 expression. The effect of the compound on TNF-induced proliferative expansion of naturally occurring Tregs (nTregs) and TGF-β-induced generation of Tregs (iTregs) from naive CD4 + Tcells was further examined., Results: A novel dimeric proaporphine alkaloid, designated as distepharinamide (DSA) with a symmetric structure isolated from the stems of D. glaucescens, restrained the doxycycline (Doxy)-induced Foxp3-tGFP expression, decreased the half-life of Foxp3 mRNA as well as reduced the mRNA levels of chemokine receptors (CCR4, CCR8 and CCR10) in Jurkat T cells with inducible Foxp3-tGFP expression. In lymphocytes or purified Tregs from wild-type C57BL/6 mice or from C57BL/6-Tg(Foxp3-DTR/EGFP)23.2Spar/Mmjax mice, DSA markedly inhibited TNF-induced proliferative expansion of Tregs present in the unfractionated CD4 + T cells, accompanied by the down-regulation of TNFR2, CD25 and CTLA4 expression on Tregs. Furthermore, DSA potently inhibited TGF-β-induced differentiation of Foxp3-expressing iTregs. Importantly, the expression of Foxp3 mRNA by both nTregs and iTregs was decreased by DSA treatment. Nevertheless, DSA at the same concentrations did not inhibit the proliferation of conventional CD4 + and CD8 + T cells stimulated by anti-CD3/CD28 antibodies., Conclusion: DSA, a novel dimeric proaporphine alkaloid, potently inhibited the expansion of nTregs and generation of iTregs. Therefore, DSA or its analogs may merit further investigation as novel immunotherapeutic agents., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

In the search for new antihepatic fibrosis candidates, it was observed that the EtOH extract of Artemisia zhongdianensis and EtOAc fraction had cytotoxicity against hepatic stellate cell line LX2 (HSC-LX2) with the inhibitory ratios of 85.7 % and 83.9 % at 400 μg/mL. 21 new guaianolide dimers, artemzhongdianolides A1 - A21 (1-21) were isolated from the active fractions under the guidance of bioassay, and elucidated by spectral analyses (HRESIMS, 1D and 2D NMR, IR, ECD). The absolute stereochemistry of compounds 1, 13, and 14 was determined by single-crystal X-ray diffraction analyses. Cytotoxicity evaluation suggested that nine compounds exhibited activity against HSC-LX2 with IC 50 values ranging from 14.0 to 95.2 μM. Of them, compounds 2, 6, and 13 displayed significant cytotoxicity against HSC-LX2 with IC 50 values of 22.1, 24.3 and 14.0 μM, which were 6 to 10 times more active than the positive drug silybin (IC 50 , 148.6 μM). Preliminary mechanism study revealed that compounds 2, 6, and 13 could markedly inhibited the deposition of human collagen type Ⅰ (Col Ⅰ), human hyaluronic acid (HA), and human laminin (HL) with IC 50 values of 37.9, 54.8, and 28.0 μM (Col Ⅰ), 29.5, 25.3, and 42.9 μM (HL), 31.2, 94.6, and 12.4 μM (HA), which were 1.5 to 13-fold more potent than silybin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

A random bioassay revealed that the EtOH extract and EtOAc fraction of Artemisia dubia Wall. (Asteraceae) exhibited cytotoxic activity against HepG2 cells with inhibitory ratios of 57.1% and 84.2% at a concentration of 100.0 μg/mL. Bio-guided isolation combined by LC-MS-IT-TOF analyses of the active fractions led to the isolation of 20 previously undescribed guaiane-type sesquiterpenoid dimers named artemidubolides A-T (1-20). Their structures and the absolute configurations were determined by comprehensive spectral analyses, comparison of the experimental and calculated ECD spectra, and seven compounds (artemidubolides A, B, D, F, K, O and R) were confirmed unequivocally by single crystal X-ray diffraction analysis. Structurally, artemidubolides A-Q were [4 + 2] Diels-Alder adducts of two monomeric guaianolides, and artemidubolides R-T were linked though an ester bond. All the isolated compounds were evaluated for their hepatomatic cytotoxicity against HepG2, Huh7, and SK-Hep-1 cell lines to demonstrate that 18 compounds exhibited obvious cytotoxicity against three tested hepatoma cell lines with IC 50 values in the range of 5.4-87.6 μM. Importantly, artemidubolides B, D, and M exhibited hepatoma cytotoxicity with IC 50 values of 5.4, 5.7, and 9.7 (HepG2), 8.2, 4.3, and 12.2 (Huh7), and 13.4, 8.4, and 12.9 μM (SK-Hep-1), respectively. Mechanism investigation in HepG2 cells suggested the most active artemidubolide D dose-dependently inhibited cell migration and invasion, induced G1/M cell cycle arrest by down-regulating proteins CDK4, CDK6 and CyclinD1 and up-regulating the level of protein P21; and induced apoptosis by down-regulated of PARP-1 and BCL-2 expression and up-regulating Bax and cleaved PARP-1 levels., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Our previous study demonstrated that paeoveitol D, a benzofuran compound isolated from Paeonia veitchii , displayed activity on MT 1 and MT 2 receptors with agonistic ratios of 57.5% and 51.6% at a concentration of 1 mM. To explore the structure-activity relationships, 34 paeoveitol D derivatives were synthesized and evaluated for their MT 1 and MT 2 agonistic activities using the Fluo-8 calcium assay. Among them, 16 and 18 derivatives increased agonistic activities on the MT 1 and MT 2 receptors, respectively. Compound 18 indicated EC 50 values of 21.0 and 298.9 μM on MT 1 and MT 2 receptors in agonistic dose response curves with Tango assays and shortened immobility time in the forced swim test. The preliminary mechanism-of-action investigation manifested that the antidepressant activity of compound 18 may be mediated by promoting serotonin (5-HT) and dopamine (DA) levels in the mice brain. Compound 18 also showed favorable pharmacokinetic profiles and low toxicity in vivo . These results suggest that compound 18 could be a potential antidepressant agent., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The dried fruit of Amomum villosum (Amomi Fructus) is an important spices and traditional Chinese medicine. In this study, the EtOH extract of Amomi Fructus was revealed with hypoglycemic effects on db/db mice by increasing plasma insulin levels. After extracted with EtOAc, the EtOAc fraction showed increased activity in stimulating glucagon-like peptide-1 (GLP-1) secretion compared with the EtOH extract. In order to clarify the antidiabetic constituents, four undescribed norlignans, amovillosumins A‒D, were isolated from the EtOAc fraction, and the subsequent chiral resolution yielded three pairs of enantiomers. Their structures were determined by extensive spectroscopic data (1D and 2D NMR, HRESIMS, IR, UV and [α] D ) and ECD calculations. Amovillosumins A and B significantly stimulated GLP-1 secretion by 375.1% and 222.7% at 25.0 μM, and 166.9% and 62.7% at 12.5 μM, representing a new type of GLP-1 secretagogues., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ten new germacrane-type sesquiterpenoids, artemyrianosins A-J (1-10), were isolated from the aerial parts of Artemisia 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 compounds 1-3, 7, and 10 showed cytotoxicity with IC 50 values ranging from 43.7 to 89.3 μM. Among them, the most active compound 3 exhibited activity against three human hepatoma cell lines with IC 50 values of 43.7 μM (HepG2), 47.9 μM (Huh7), and 44.9 μM (SK-Hep-1)., (© 2022. The Author(s).)

Ten new diarylheptanoid dimers, katsumadainols C 1  - C 10 (1-10), were isolated from the seeds of Alpinia katsumada and elucidated by extensive spectroscopic methods, ECD calculations, and single-crystal X-ray diffraction. Their antidiabetic effects were evaluated by the stimulation of GLP-1 secretion in STC-1 cells and inhibition against four diabetes-related enzymes, GPa, α-glucosidase, PTP1B, and DPP4. Compounds 1-5 and 7-10 significantly stimulated GLP-1 secretion by 267.5-433.1% (25.0 μM) and 117.8-348.2% (12.5 μM). Compounds 1-4 exhibited significant inhibition on GPa with IC 50 values of 18.0-31.3 μM; compounds 1-5 showed obvious inhibition on α-glucosidase with IC 50 values of 6.9-18.2 μM; compounds 1-5 and 10 possessed PTP1B inhibitory activity with IC 50 values ranging from 35.5 to 80.1 μM. This investigation first disclosed compounds 1-4 as intriguing GLP-1 secretagogues and GPa, α-glucosidase, and PTP1B inhibitors, which provided valuable clues for searching multiple-target antidiabetic candidates from Zingiberaceae plants., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The dammarane triterpenoid (20 S ,24 R )-epoxy-dammarane-3 β ,12 β ,25-triol obtained from Cyclocarya paliurus in our previous study showed inhibitory activity on α -glucosidase in vitro with an inhibitory ratio of 32.2% at the concentration of 200 μM. In order to reveal the structure-activity relationships (SARs) and get more active compounds, 42 derivatives of (20 S ,24 R )-epoxy-dammarane-3 β ,12 β ,25-triol were synthesized by chemical modification on the hydroxyls (C-3 and C-12), rings A and E, and assayed for their α -glucosidase and PTP1B inhibitory activities. Two compounds ( 8 , 26 ) increased activity against α -glucosidase, and four compounds ( 8 , 15 , 26 , 42 ) significantly inhibited PTP1B. It was noted that compounds 8 and 26 could inhibit both α -glucosidase and PTP1B as dual-target inhibitors with IC 50 values of 489.8, 467.7 μM ( α -glucosidase) and 319.7, 269.1 μM (PTP1B). Compound 26 was revealed to be a mix-type inhibitor on α -glucosidase and a noncompetitive-type inhibitor on PTP1B based on enzyme kinetic study. Furthermore, compound 42 could selectively inhibited PTP1B as a mix-type inhibitor with IC 50 value of 134.9 μM, which was 2.5-fold higher than the positive control, suramin sodium (IC 50 339.0 μM), but not inhibit α -glucosidase., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

Our previous study demonstrated that guaiane-type sesquiterpenoid ludartin showed potent antihepatoma activity against two human hepatocellular carcinoma cell lines, HepG2 and Huh7, with IC 50 values of 32.7 and 34.3 μM, respectively. In this study, 34 ludartin derivatives were designed, synthesized and evaluated for their cytotoxic activities against HepG2 and Huh7 cell lines using an MTT assay in vitro. As a result, 17 compounds increased the activity against HepG2 cells, and 20 compounds enhanced the activity against Huh7 cells; 14 derivatives 2, 4-7, 9, 11, 17, 24, 28-30 and 32-33 were superior to ludartin on both HepG2 and Huh7 cells. In particular, dimeric derivative 33 as the most active compound showed 20-fold and 17-fold enhancement of cytotoxicity against HepG2 and Huh7 cells compared to that of ludartin. These results suggested that compound 33 could serve as a promising lead compound against liver cancer. Graphical abstract., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

The antidepressant activity of (+) and (-)-paeoveitol was first evaluated using the forced swimming test (FST), and (+)-paeoveitol showed potential antidepressant activity by decreasing immobility time of mice (by approximately 26.4%) in the FST at a dose of 20 mg/kg. To explore the structure-activity relationships (SARs) and obtain more potent compounds, twenty derivatives of (+)-paeoveitol were synthesized and evaluated for their agonistic activities on melatonin type I (MT 1 ) and type II (MT 2 ) receptors. As a results, compound 13 with an N -methylpiperazine fragment exhibited obvious effect on MT 1 and MT 2 receptors with EC 50 values of 0.20 and 0.24 mM. Moreover, compound 13 dose-dependently decreased the immobility of mice in the FST and showed an inverted U-shaped dose-effect, and the most efficacious dose (at 40 mg/kg) was comparable to fluoxetine (20 mg/kg) with a reduced immobility time of 29.2% and 34.5%, respectively. In vivo neurochemical assays suggested that compound 13 obviously increased 5 - hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in the mice brain, indicating that its antidepressant effects might be related to the monoaminergic system. In silico ADMET study revealed that 13 has favorable pharmacokinetic properties. These findings suggest that compound 13 could be a potential antidepressant agent. Graphical abstract., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Under the guidance of bioassay against HSC-LX2, the EtOH extract and the EtOAc fraction of Artemisia capillaris (Yin-Chen) exhibited cytotoxic activity against HSC-LX2 with inhibitory ratios of 39.7% and 68.7% at the concentration of 400.0 μg/mL. Bioassay-guided investigation of Fr. D (the active fraction) yielded 14 new coumaric acid analogues, artemicapillasins A-N (1-14). The structures of the isolates were elucidated by spectroscopic analyses involving UV, IR, MS, 1D and 2D NMR spectra and ECD calculations. Cytotoxic activity against HSC-LX2 cells of these isolates was performed to reveal that 12 compounds demonstrated cytotoxicity with inhibitory ratios more than 50% at 400 μM. The most active artemicapillasin B (2) gave an IC 50 value of 24.5 μM, which was about 7 times more toxic than the positive drug silybin (IC 50 , 162.3 μM). Importantly, artemicapillasin B (2) showed significant inhibition on the deposition of human collagen type I (Col I), human laminin (HL) and human hyaluronic acid (HA) with IC 50 values of 11.0, 14.4 and 13.8 μM, which was about 7, 11 and 5 times more active than silybin. Artemicapillasin B (2) as an interesting antihepatic fibrosis candidate is worth in-depth study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The biomimetic synthesis of guaianolide dimers lavandiolides H, I, and K and artematrolide F containing a spirolactone moiety has been accomplished for the first time from naturally abundant arglabin in four to six steps with an overall yield up to 60%, and a series of natural product-like guaianolide dimers, trimer, and tetramer were also successfully synthesized. Notably, the trimeric compound exhibited antihepatoma cytotoxicity more potent than that of sorafenib with IC 50 values of 6.2 μM (HepG2), 6.8 μM (Huh7), and 7.2 μM (SK-HEP-1).

Random screening revealed that the EtOH extract of Artemisia atrovirens showed significant cytotoxicity against two human hepatoma cell lines (HepG2 and Huh7) with the inhibitory ratio of 98.9% and 99.7% at the concentration of 100 μg/mL. Further bioactivity-guided isolation of active fraction led to 16 new guaiane-type sesquiterpenoids, artematrovirenins A-P (1-16). Their structures were elucidated by extensive spectroscopic data. The absolute stereochemistry of compounds 1 and 14 was determined by single-crystal X-ray diffraction analyses. Pharmacological evaluation suggested that five compounds (3, 5, 8, 10, and 15) exhibited cytotoxicity, compounds 3 and 5 displayed cytotoxicity against HepG2 cell line with an IC 50 values of 8.0 and 16.0 μM, as well as against Huh7 cell line with values of 18.2 and 32.2 μM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Liver fibrosis is a final result of extensive deposition of extracellular matrix (ECM) and starts with the activation and proliferation of hepatic stellate cells (HSCs). Our previous study showed that eudesmane sesquiterpenoid santamarin had cytotoxicity against hepatic stellate cell line LX2 (HSC-LX2) with IC 50 values of 16.5 ± 0.7 μM. To explore the structure-activity relationships, twenty-six derivatives were synthesized by modifying the hydroxyl group, double-bond and unsaturated lactone. Cytotoxicity evaluation suggested that eight derivatives (6, 9, 13, 17, 20 and 25-27) increased activity against HSC-LX2. Especially, derivatives 17, 20 and 25 displayed obvious cytotoxicity with IC 50 values of 6.4 ± 0.4, 4.6 ± 0.1, and 3.5 ± 0.1 μM, which were 3 to 5-fold higher than santamarin. Preliminary mechanisms study revealed that the active compound 20 exhibited more than 8-fold and 6-fold enhancement of inhibitory effect on the deposition of human hyaluronic acid (HA) and human laminin (HL) with IC 50 values of 7.6 ± 0.6 and 3.3 ± 1.2 μM., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The EtOH extracts of the dried seeds of Alpinia katsumadai were revealed with hypoglycemic effects on db/db mice at the concentration of 200 mg/kg. In order to clarify the antidiabetic constituents, 16 new diarylheptanoid-chalcone hybrids, katsumadainols A 1 -A 16 (1-16), together with 13 known analogues (17-29), were isolated from A. katsumadai under the guidance of bioassay. Most of the compounds showed α-glucosidase and PTP1B dual inhibition, among which compounds 1-3, 5-7, 11-14, 21-25, and 27 showed PTP1B/TCPTP selective inhibition with IC 50 values ranging from 22.0 to 96.7 μM, which were 2-10 times more active than sodium orthovanadate (IC 50 , 215.7 μM). All compounds exhibited obvious inhibition against α-glucosidase with IC 50 values of 2.9-29.5 μM, indicating 6-59 times more active than acarbose (IC 50 , 170.9 μM). Study of enzyme kinetics indicated compounds 1, 3, and 12 were PTP1B and α-glucosidase mixed-type inhibitors with K i values of 13.1, 12.9, 21.6 μM, and 4.9, 7.4, 3.4 μM, respectively., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Artatrovirenols A and B ( 1 and 2 ), two novel cagelike sesquiterpenoids, possess a unique 5/5/6/5/5-pentacyclic and a 5/5/6/5-tetracyclic system with an unprecedented tetracyclo[5.3.1.1. 4,11 0 1,5 ]dodecane scaffold from Artemisia atrovirens . The structures of compounds 1 and 2 including their absolute stereochemistry were elucidated through extensive spectroscopic analyses, X-ray crystallography, and quantum chemical calculations. Plausible biosynthetic pathways for the new isolates were proposed from the naturally occurring arglabin ( 3 ) via the key intramolecular Diels-Alder cycloaddition. Compound 1 showed cytotoxicity against three human hepatoma cell lines (HepG2, SMMC-7721, and Huh7) with half maximal inhibitory concentration values of 123.8, 44.0, and 142.6 μΜ, respectively.

The dried fruits of Amomum tsao-ko were first revealed to have hypoglycemic effects on db/db mice at a concentration of 200 mg/kg. In order to clarify the antidiabetic constituents, 19 new flavanol-fatty alcohol hybrids, tsaokoflavanols A-S ( 1-19 ), were isolated and determined by extensive spectroscopic data and ECD calculations. Most of the compounds showed α-glucosidase and PTP1B dual inhibition, among which 1 , 2 , 6 , 11 , and 18 exhibited obvious activity against α-glucosidase with IC 50 values of 5.2-9.0 μM, 20-35 times stronger than that of acarbose (IC 50 , 180.0 μM); meanwhile, 6 , 10 - 12 , and 19 were PTP1B/TCPTP-selective inhibitors with IC 50 values of 56.4-80.4 μM, 2-4 times stronger than that of suramin sodium (IC 50 , 200.5 μM). Enzyme kinetics study indicated that compounds 1 , 2 , 6 , and 11 were α-glucosidase and PTP1B mixed-type inhibitors with K i values of 13.0, 11.7, 2.9, and 5.3 μM and 142.3, 88.9, 39.2, and 40.8 μM, respectively. Docking simulations proved the importance of hemiacetal hydroxy, the orientation of 3,4-dihydroxyphenyl, and the length of alkyl in binding with α-glucosidase and PTP1B.

The preliminary assay suggested that the EtOH extract of Artemisia lavandulaefolia had cytotoxicity against hepatic stellate cell line LX2 (HSC-LX2) with an inhibitory ratio of 94.1% at 400 μg/mL. Bioassay-guided investigation led to eleven new sesquiterpenoids, artemilavanolides C-F (1-4) and artemlavandulolides A-G (5-11), as well as thirteen known compounds (12-24). Their structures were elucidated by extensive spectroscopic data and X-ray crystallographic analysis. Cytotoxicity evaluation suggested that fourteen compounds exhibited activity against HSC-LX2; compounds 22, 23 and 24 were comparable to the positive control, silybin (IC 50 , 162.3 μM); compounds 6, 9 and 16 showed moderate activity with IC 50 values of 109.3, 114.0 and 124.2 μM. Importantly, compounds 14, 15 and 18 displayed significant cytotoxicity against HSC-LX2 with IC 50 values of 52.1, 16.5 and 21.3 μM, and inhibitory activity on the deposition of human collagen type I (Col I) and human laminin (HL) with IC 50 values ranging from 7.3 to 71.6 μM and from 18.6 to 72.9 μM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Random screening suggested that the EtOH extract of Artemisia myriantha (Asteraceae) and its EtOAc fraction had cytotoxicity against HepG2 cells with inhibitory ratios of 30.6% and 53.5% at 50.0 μg/mL. Bioassay-guided isolation of the most active fractions (Fr. C and Fr. D) afforded 19 new sesquiterpenolides, artemyrianolides A-S ( 1 - 19 ), involving 13 germacranolides ( 1 - 13 ), four guaianolides ( 14 - 17 ), and two eudesmanolides ( 18 and 19 ), together with 16 known sesquiterpenoids ( 20 - 35 ). The new compounds were characterized by physical data analyses (HRESIMS, IR, 1D and 2D NMR, ECD), and the absolute configurations of compounds 1 , 2 , and 11 were determined by X-ray crystallography. Structurally, compounds 2 and 11 - 13 maintain an uncommon cis -fused 10/5 bicyclic system and compound 12 possesses an unusual (7 S ) configuration. Twenty of the compounds exhibited cytotoxicity against HepG2, Huh7, and SMMC-7721 cell lines. Compound 9 showed cytotoxic activity on both HepG2 and Huh7 cells with IC 50 values of 8.6 and 8.8 μM, and compounds 8 and 33 showed cytotoxicity to the three human hepatoma cell lines with IC 50 values of 4.9 and 7.4 μM (HepG2), 4.3 and 7.8 μM (Huh7), and 3.1 and 9.8 μM (SMMC-7721), respectively.

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 IC 50 values ranging from 33.3 to 145.2 μM.

Two new sesquiterpenoids, artemlavanins A (1) and B (3), together with fifteen known compounds (2 and 4-17) were isolated 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-hydroxyacetophenone moiety. Twelve compounds (1-3, 5-7, 10-12, 14, 15 and 17) displayed cytotoxicity against hepatic stellate cell line LX2 (HSC-LX2) with IC 50 values ranging from 35.1 to 370.3 μM. Compounds 2, 7, 10-12 and 17 exhibited the stronger cytotoxicity than silybin (IC 50 , 169.6 μM) with IC 50 values of 82.1, 35.1, 95.0, 83.8, 81.6 and 90.1 μM. 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 IC 50 values of 10.7, 24.5 and 13.3 μM.

Spiroseoflosterol ( 1 ), a 7(8→9)- abeo -ergostane steroid with a unique spiro[4.5]decan-6-one system, was isolated from the fruiting bodies of Butyriboletus roseoflavus . Its structure was determined by interpretation of comprehensive spectroscopic, X-ray, and computational data. A plausible biogenetic pathway for spiroseoflosterol ( 1 ) was postulated based on a key semipinacol rearrangement. Compound 1 was cytotoxic to HepG2 and Huh7/S (sorafenib-resistant Huh7) with IC 50 values of 9.1 and 6.2 μM, respectively.

The ent-kaurane diterpenoid chepraecoxin A (CA) obtained in our previous study showed a potential inhibitory activity on α-glucosidase (IC 50 274.5 ± 12.5 μM). In order to figure out the structure-activity relationships (SARs), twenty-two derivatives of chepraecoxin A were synthesized by modifying the ester, allyl, double bond and carboxyl groups, and assayed for their α-glucosidase inhibitory activity. Of them, eight compounds (14-17, 19-22) significantly increased activity with IC 50 values ranging from 16.1 to 71.4 μM, even higher than the positive control, acarbose (IC 50 130.3 μM). Especially, compounds 17, 19 and 21 could inhibit α-glucosidase with IC 50 values of 16.9 ± 3.4, 16.1 ± 1.2, and 17.1 ± 0.6 μM, 17-fold higher than CA. The most active compound 19 was proven to be a non-competitive inhibitor with a K i value of 19.4 μM based on enzyme kinetics study. The primary SARs of CA derivatives were summarized for exploring antidiabetic candidates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Over the past few years, artificial enzymes have attracted enormous attention due to their high stabilities and cost-effective productions. In this work, metal-organic framework-derived SiW 12 @Co 3 O 4 was synthesized in large quantities by stirring the mixture at ambient temperature and calcination. The obtained SiW 12 @Co 3 O 4 exhibited a highly inherent peroxidase-like activity and excellent stability. Kinetic studies demonstrated that the synthesized SiW 12 @Co 3 O 4 had a strong binding affinity to 3,3',5,5'-tetramethylbenzidine (TMB), stronger than HRP had. Specifically, the peroxidase-like activity of SiW 12 @Co 3 O 4 in an aqueous solution was well maintained after incubation at an elevated temperature, at an extreme pH and for a long time. A SiW 12 @Co 3 O 4 -based method was further developed for H 2 O 2 and one-pot glucose detection with good sensitivity and reliability. The facile synthesis approach is expected to facilitate the practical use of metal-organic frameworks and their derivatives as enzyme mimics in the future.

Gastrodia elata is a famous traditional Chinese herb with medicinal and edible application. In this study, nine polybenzyls (1-9), including six new ones (2-5, 7 and 9), were isolated from the EtOAc extract of G. elata. Five compounds 1, 3, 4, 6 and 8 were found to activate melatonin receptors. Especially, compound 1 showed agonistic effects on MT 1 and MT 2 receptors with EC 50 values of 237 and 244 μM. For better understanding their structure-activity relationships (SARs), ten polybenzyl analogs were further synthesized and assayed for their activities on melatonin receptors. Preliminary SARs study suggested that two para-hydroxy groups were the key pharmacophore for maintaining activity. Molecular docking simulations verified that compound 1 could strongly interact with MT 2 receptor by bonding to Phe 118, Gly 121, His 208, Try 294 and Ala 297 residues., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Artemisia capillaris (Yin-Chen) is a famous traditional Chinese medicine (TCM) for treating acute and chronic hepatitis in China. Enynes are one type of characteristic constituents in this herb, while their anti-hepatitis B virus (anti-HBV) properties have not been systemically investigated., Aim of the Study: This study is to reveal the active part of A. capillaris, and systemically investigate the enynes and their anti-HBV activity., Materials and Methods: The total extract and each fraction of A. capillaris were assayed for the anti-HBV activity to reveal the active part. Bioassay-guided fractionation using various chromatographic techniques yielded the enynes, whose structures were elucidated by spectroscopic analyses and ECD calculations. The anti-HBV properties inhibiting HBsAg and HBeAg secretions and HBV DNA replication were evaluated on HepG 2.2.15 cell line in vitro., Results: ACT-2 and ACT-3 was revealed to be the respective active and toxic part of A. capillaris. Twelve enynes (1-12) involving four new ones (1-4) and two unusual enyne analogs (13-14) were isolated from the active part (ACT-2). All the isolates were assayed for their anti-HBV activity, and the preliminary structure-activity relationships were summarized based on the structural features. In particular, compound 4 could significantly inhibit the secretions of HBsAg and HBeAg, and HBV DNA replication with IC 50 values of 197.2 (SI > 5.1), 48.7 (SI > 20.5) and 9.8 (SI > 102) μM., Conclusions: Enynes are responsible for the anti-HBV effects of A. capillaris. Hydroxyl and glycosyl groups are preferable for maintaining activity. This is the first time to systematically investigate the anti-HBV activity of enynes in A. capillaris, which provides valuable information for understanding the ethnopharmacological application of Yin-Chen., (Copyright © 2018. Published by Elsevier B.V.)

Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC 50 values of 396.5 and 383.0 μM agitating on MT 1 and MT 2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Ten new (1-10) and ten known (11-20) diterpenoids involving ent-atisane, ent-seco-atisane, ent-kaurane and ent-seco-kaurane types were isolated from Sapium insigne under the guidance of LCMS-IT-TOF analyses. Their structures were characterized by extensive spectroscopic analyses (HRESIMS, UV, IR, 1D and 2D NMR). A putative biosynthetic pathway was proposed for ent-seco-atisane diterpenoids. Their inhibitory activities on α-glucosidase in vitro were tested for the first time. Compound 4 showed moderate inhibitory effect on α-glucosidase with an IC 50 value of 0.34 mM via a noncompetitive inhibition mechanism (K i  = 0.27 mM). The preliminary structure-activity relationships of the ent-atisane diterpenoids inhibiting α-glucosidase were discussed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Twenty-four gramine derivatives were synthesized and evaluated on MT 1 and 5-HT 1A receptors in vitro. Among them, seven derivatives (7, 8, 16, 19, 20, 21, and 24) exhibited higher agonisting activities on MT 1 or 5-HT 1A receptors. Compared with gramine, derivatives 7, 8, 16, 19, 20, 21, and 24 displayed 1.6-3.5-fold increase in agonistic rates on 5-HT 1A receptor. Particularly, derivatives 7, 19, and 21 exhibited significant agonistic activities on MT 1 and 5-HT 1A receptors with EC 50 values of 0.51, 0.39, 0.50 mΜ and 0.28, 0.46, 0.23 mΜ, respectively. The preliminary structure-activity relationships of gramine derivatives were summarized for further investigation on MT 1 and 5-HT 1A receptors as new potential agonists.

(±)-Uncarilins A and B (1a/1b and 2a/2b), two pairs of unusual dimeric isoechinulin-type enantiomers with a symmetric four-membered core, were isolated from Uncaria rhynchophylla driven by LCMS-IT-TOF analyses. Their structures were elucidated by extensive 1D and 2D NMR spectra, X-ray diffraction, and ECD spectroscopic data. (-)-Uncarilin B (2a) showed activities on MT 1 and MT 2 receptors with agonistic rates of 11.26% and 52.44% at a concentration of 0.25 mM.

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 μM. Particularly, derivative 6 showed significant activities with IC 50 values of 3.39, 13.59, 6.65, 13.09 and 12.38 μM respectively against HL-60, A-549, SMMC-7721, MCF-7 and SW480 cells, which suggested more potent activities than that of cis-dichlorodiamineplatinum (DDP).

The first catalytic asymmetric total synthesis of (+)- and (-)-paeoveitol has been accomplished in 42% overall yield via a biomimetic hetero-Diels-Alder reaction. The chiral phosphoric acid catalyzed hetero-Diels-Alder reaction showed excellent diastereo- and enantioselectivity (>99:1 dr and 90% ee); two rings and three stereocenters were constructed in a single step to produce (-)-paeoveitol on a scale of 452 mg. This strategy enabled us to selectively synthesize both paeoveitol enantiomers from the same substrates by simply changing the enantiomer of the catalyst.

1,2-Diketones are employed, for the first time, as electrophiles in the vinylogous aldol reaction. With 5 mol% of chiral tertiary amine-thiourea , a direct vinylogous aldol-cyclization cascade reaction between β,γ-unsaturated amides and o-quinones has been achieved to produce spirocyclic dihydropyranones in 76-99% yield and 82-95% ee.

The first enantioselective aza-Morita–Baylis–Hillman reaction of acrylates with ketimines derived from isatins has been developed. With 2 mol% of chiral bifunctional phosphine-squaramide 4e, optically active 3-substituted-3-amino-2-oxindoles were obtained in excellent yields with up to 91% ee.

The first enantioselective vinylogous aldol-cyclization cascade reaction of allyl pyrazoleamides with isatins is reported. With 1 mol% of Takemoto catalyst, optically active spirocyclic oxindole-dihydropyranones were obtained in excellent yields (93-99%) and good-to-excellent enantioselectivities (82-97% ee).