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Comprehensive Summary: Ten novel isocoumarins, including four pairs of enantiomers, were isolated from Artemisia dubia var. subdigitata (Asteraceae). Compounds 1, 2 and 3a/3b possessed a unique 6/6/6‐tricyclic system comprising an unusual 1‐(2‐methylcyclohexyl) propan‐1‐one moiety fused with isocoumarin core skeleton. Compounds 4a/4b were characterized as an unexpected 2,5‐dimethylcyclohexan‐1‐one scaffold, and compounds 5a/5b and 6a/6b were rare 1,2‐seco‐isocoumarin. Their structures and absolute configurations were elucidated through spectroscopic data, X‐ray crystallography, ECD and NMR calculations with DP4+ analyses. Plausible biosynthetic pathways were proposed from the naturally occurring isocoumarin. Network pharmacological analysis suggested that the targets of compound 1 were significantly enriched in the cell cycle and PI3K‐Akt signaling pathway. The molecular docking revealed that compound 1 had high binding affinity with CDK2 (total score: 6.8717). Furthermore, compounds 1 and 2 exhibited inhibitory activity on three human hepatoma cell lines, with inhibitory ratios of 85.1% and 84.5% (HepG2), 88.2% and 87.3% (Huh7), and 69.2% and 69.1% (SK‐Hep‐1) at 200 μmol·L–1, respectively. [ABSTRACT FROM AUTHOR]

A catalytic asymmetric vinylogous aldol reaction between β,γ-unsaturated amides and isatins has been developed. In the presence of 10 mol% of tertiary amine-thiourea C7, the vinylogous reaction has been achieved in up to 98% yield and up to 99% ee (26 examples). This methodology provides an efficient approach to construct chiral multifunctional 3-hydroxy-2-oxindoles. Moreover, the transformations of the chiral products, including the esterification of amides, the hydrogenation of the C–C double bond and further conversion to spirolactones, have been investigated. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Nineteen new cadinane‐involving sesquiterpenoid dimers, artemordins A—S (1—19), together with 13 known SDs (20—32) were isolated from Artemisia ordosica. Their structures and absolute configurations were established by comprehensive spectral analyses, X‐ray single crystal diffraction, theoretical ECD, and NMR calculations. Chemically, artemordins A—F (1—6) were the first examples of two cadinane units constructed by unprecedented C‐3−C‐15′ or C‐3−C‐13′ single bond with an oxido‐rearranged 6/5/6/6 fused ring system; artemordins G—K (7—11) were biogenetically connected by [4 + 2] cycloaddition reaction and artemordins G—J (7—10) possessed a novel 5/6/6/6/6/6/5‐heptacyclic fused ring system. Artemordins L—S (12—19) were formed by esterification, which involved three different types of sesquiterpenoids. Antihepatoma assay suggested that the most active compounds, artemordins B and H (2 and 8), exhibited inhibitory activities on three hepatoma cell lines with IC50 values of 26.9 and 25.1 μmol/L (HepG2), 29.5 and 18.3 μmol/L (Huh7), 19.7 and 15.7 μmol/L (SK‐Hep‐1). [ABSTRACT FROM AUTHOR]

In the field of molecular nonequilibrium transports, physical mechanisms of multiple reaction dynamics of these systems are the core of deep understanding complex reactions and transport mechanisms. In order to explore related mechanisms, establishing multiple systems coupled with tremendous exit dynamics and studying their exit dynamics properties are quite vital. Beyond previous researches, new stochastic transport processes are emphasized here. Multiple new exit dynamic systems are established, which are motivated by the multiplicity of paths and products of real biochemical processes in organisms. In order to ensure research universality, core system modeling factors are fully considered. Countable parallel orbits, uniform connection with external sources, countable parallel orbits as subsystems in middle lattices and influences of all lattices on transport trajectories on dynamic properties are analyzed. Dynamic properties of different particles located in orbits are explored by deeply studying average exit time and time scale. Quantitative spatiotemporal impacts are extensively studied. The rationality of average exit time as a time scale in the universal exit dynamic system is proved. Main findings and fruitful results can not only serve as theoretical bases for broadening reaction path modeling, but also be helpful to support understanding nonequilibrium transport mechanisms, especially stochastic biochemical processes. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Eight new guaiane‐type sesquiterpenoid trimers, artemsieverolactones A—H, possessing unprecedented scaffolds via biocatalyzed [4+2] Diels−Alder cycloaddition reactions were identified from Artemisia sieversiana. Their structures were determined by comprehensive spectroscopic data, single‐crystal X‐ray diffraction analyses, and ECD calculations. In terms of structure, artemsieverolactones A—H are first examples of sesquiterpenoid trimers from guaiane‐type sesquiterpenoid through four different [4+2] Diels−Alder cycloaddition models. Antihepatic fibrosis assay suggested that five compounds exhibited activity against HSC‐LX2 with IC50 values ranging from 37.8 to 117.1 μmol/L. The most active artemsieverolactone B (2) displayed significant inhibitory activity against HSC‐LX2 with IC50 value of 37.8 μmol/L, which was 3 times more active than the positive drug silybin (IC50, 139.7 μmol/L). Preliminary mechanism study revealed that artemsieverolactone B could inhibit the deposition of human collagen type I (Col I), human hyaluronic acid (HA), and human laminin (HL) with IC50 values of 40.4 μmol/L (Col I), 55.1 μmol/L (HL), 47.3 μmol/L (HA), which was 2 to 3‐fold more potent than silybin. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: 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 IC50 values in the range of 5.0—67.3 μmol/L. Interestingly, compound 1 manifested significant cytotoxicity against HepG2, Huh7, and SK‐Hep‐1 cells with IC50 values of 9.9, 9.2, and 5.0 μmol/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. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: 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 IC50 values ranging from 9.9 to 170.1 μmol/L. Importantly, artemzhongdianolide B9 (9) was the most active one against three hepatoma cell lines with IC50 values of 13.1 μmol/L (HepG2), 19.5 μmol/L (Huh7), and 19.5 μmol/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. [ABSTRACT FROM AUTHOR]

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 IC50 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. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: 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 62.3 μmol/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 19.4 μmol/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. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: 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 100 μg/mL, respectively. Bioactivity‐guided isolation afforded 15 new diarylheptanoid‐flavanone hybrids, katsumadainols B1—B15 (1—15), together with eight known ones (16—23). Compounds 4—10 and 12—21 exhibited activity against GPa with IC50 values of 10.1—95.4 μmol/L; compounds 4, 5, 16, and 17 displayed inhibitory effects on α‐glucosidase with IC50 values of 7.1, 12.4, 7.2, and 8.3 μmol/L, obviously higher than acarbose (IC50, 209.1 μmol/L); compounds 4—6, 14, 16—20, 22, and 23 were PTP1B/TCPTP selective inhibitors with IC50 values of 40.7—95.8 μmol/L; compounds 4, 5, 16, and 17 showed DPP4 inhibitory effects with inhibitory ratios of 50.0%—54.2% (200 μmol/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. [ABSTRACT FROM AUTHOR]

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 SiW12@Co3O4 was synthesized in large quantities by stirring the mixture at ambient temperature and calcination. The obtained SiW12@Co3O4 exhibited a highly inherent peroxidase-like activity and excellent stability. Kinetic studies demonstrated that the synthesized SiW12@Co3O4 had a strong binding affinity to 3,3′,5,5′-tetramethylbenzidine (TMB), stronger than HRP had. Specifically, the peroxidase-like activity of SiW12@Co3O4 in an aqueous solution was well maintained after incubation at an elevated temperature, at an extreme pH and for a long time. A SiW12@Co3O4-based method was further developed for H2O2 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. [ABSTRACT FROM AUTHOR]

• Rubiginosin B (RGB) and two new meroterpenoids were isolated from R. brachypodum. • Rhodobrachypodic acid was proposed as the precursor of RGB. • RGB selectively inhibits the differentiation of Treg cells. • RGB enhances anti-tumor immune responses and inhibits the growth of tumor in mice. • RGB inhibits Foxp3 expression through calcineurin-NFAT signaling. 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. To identify small-molecule inhibitors of Tregs from R. brachypodum. 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. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]