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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: 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: 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]

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. [ABSTRACT FROM AUTHOR]

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.)

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.)