A phytochemical investigation on the twigs and leaves of Excoecaria agallocha led to the discovery of eight undescribed diterpenoids, along with 21 known analogues. Their structures were elucidated based on comprehensive HRESIMS, HREIMS, and NMR spectroscopic analyses. The cytotoxicity of some isolates was tested against human lung cancer cells (A549) and human promyelocytic leukemia cells (HL-60). Compounds 2 and 4 showed moderate cytotoxic effect against HL-60 with IC50 values of 7.60 ± 2.67 μM and 12.64 ± 0.13 μM, respectively. However, other tested compounds displayed little or weak inhibitory effects against A549 and HL-60 with inhibition rate less than 50% at the concentration of 20 μM.

Human carboxylesterase 2A (hCES2A) is a key mediator of drug metabolism and chemotherapeutic side effects, necessitating potent and selective inhibitors. Herein, 42 novel steroid derivatives were rationally designed via hCES2A homology modeling and synthesized. Compound 3g emerged as the lead inhibitor, exhibiting strong hCES2A inhibitory activity (IC₅₀ = 1.257 μM) and excellent selectivity, with no cross-inhibition on hCES1A, hAchE, or hBchE. Structure-activity relationship (SAR) analysis and a validated 3D-QSAR model identified steric and hydrophobic effects as key activity determinants. Mechanistic studies confirmed 3g acts as a competitive inhibitor (Ki = 1.503 μM) with favorable binding affinity (Kd = 1.00 μM). Molecular docking revealed 3g occupies the hCES2A catalytic triad (Ser-228, Glu-345, His-457) pocket, stabilized by π-π stacking with Phe-106/Phe-469. Critical cellular validation was performed via high-content imaging, which confirmed specific hCES2A inhibition in HepG2 cells. Additionally, 3g exhibits low cytotoxicity and good metabolic stability. In conclusion, compound 3g was identified as a potent inhibitor of hCES2A.

Ten undescribed sesquiterpenoids were isolated from Chloranthus japonicus Sieb., including (4R,5S,6R,8R,10R)-4- hydroxy-6-O-(3-D-glucosyleudesman-7(11)-en-8,12-olide (1), (1R,4R,5R,8S,10R)-1,4-dihydroxy-15-(2-methyl- butyryloxy)eudesman-7(11)-en-8,12-olide (2),(1R,4S,5R,8S,10R)-1,4-dihydroxy-15-(2-methylbutyryloxy)eudes- man-7(11)-en-8,12-olide (3), (1R,3S,4R,5S,8S,9S,10S)-8,9-epoxy-15-hydroxylindenran-7(11)-en-8,12-olide (4), (1R,3S,4R,5S,8S,9S,10S)-8,9,15-trihydroxylindenran-7(11)-en-8,12-olide (5), (1R,3S,4R,5S,6R,8S,10S)-6-ace- toxyl-4-hydroxy-15-O-(3-D-glucosyllindenran-7(11)-en-8,12-olide (6), (1R,3S,4R,5S,6R,8S,10S)-15-hydroxy-4-O- (3-D-glucosyllindenran-7(11),8(9)-dien-8,12-olide (7), japonilides A-C (8-10), along with 19 known compounds. Compounds 8-10 are rare 5,6-seco-germacrane-type sesquiterpenoids, and only one of this type sesquiterpenoid has been reported to be isolated from C. anhuiensis. 9-Ketocurzerene (27) was first reported from a natural source. The structures and absolute configurations of the compounds were elucidated through a combination of spectroscopic data interpretation, quantum-chemical calculation, DP4+ probability analysis, and single-crystal X-ray diffraction analysis. Compounds 8, 12, 16 and 22 exhibited significant inhibitory effects on NO production in lipopolysaccharide-stimulated RAW 264.7 macrophages, with IC50 values of 22.99 +/- 2.71, 24.34 +/- 1.36, 23.69 +/- 2.83, and 21.23 +/- 1.34 mu mol/L, respectively. Western blotting studies demonstrated that compound 8 inhibited the expression of nitric oxide synthase and cyclooxygenase-2, which act as key mediators in the inflammatory response.

Chemical investigation of the twigs and leaves of Euphorbia tirucalli afforded six undescribed tigliane glycosides, tirucalosides A-F (1-6), together with 12 known diterpenoids (7-18). Compound 1 represents a rare carbon skeleton bearing a 5/7/5/4-fused ring system, while compound 6 contains an unusual seco-glucoside substitution. Their structures were determined by a combination of an extensive spectroscopic analysis and acid hydrolysis experiment. Compounds 1-5 reversed multidrug resistance on adriamycin-resistant K562/ADR cells with the fold-reversals ranging from 17.4 to 64.6 at the noncytotoxic concentration of 10 μM. The rhodamine 123 efflux assays revealed that compound 1 inhibited the P-glycoprotein (P-gp) transporter function, thus reversing the drug resistance.

Comprehensive Summary Seventeen undescribed lindenane‐related sesquiterpenoid dimers, chlorajaponins A—Q ( 1 — 17 ), and 13 reported analogs ( 18 — 30 ) were isolated from Chloranthus japonicus Sieb. Compound 1 possesses an unprecedented 3/5/7/5/5/6/5/3 fused octacyclic scaffold, featuring a 6(5→4)‐ abeo ‐lindenane monomer, while 2 exhibits a 3/5/6/6/5/6/5/3 fused octacyclic scaffold. Their structures were determined through a combination of spectroscopic analyses and X‐ray crystallography. Compounds 1 , 2 , and 18 demonstrated significant inhibitory effects on lipid accumulation and effectively reduced the levels of triglycerides and total cholesterol, as well as the levels of aspartate aminotransferase and alanine aminotransferase in a HepG2 cell model. In addition, compounds 1 , 2 , and 18 significantly suppressed the protein expression of the fatty acid synthase (FASN) and the sterol regulatory element‐binding protein 1 (SREBP1). Moreover, the anti‐inflammatory assay showed that compounds 19 — 22 and 25 inhibited the NO production induced by lipopolysaccharide in RAW 264.7 macrophages with IC 50 values of 7.89 ± 0.44, 6.25 ± 0.46, 2.98 ± 0.29, 10.77 ± 0.60, and 3.60 ± 0.28 μmol/L.

Phytochemical investigation of the whole herbs of Euphorbia humifusa Willd. led to the isolation of two unde-scribed triterpenoids, (3S,5R,7R,8S,10S,13S,14S,17R,18R,21R)-7 alpha,8 alpha-epoxyfern-9(11)-en-3 beta-ol (1) and (3R, 7R,8S,9S,13S,14S,17R,18R,21R)-7 alpha,8 alpha-epoxyadian-5(10)-en-3 alpha-ol (2), along with three known compounds 3-5. Their structures were elucidated by spectroscopic analysis and optical rotation calculations. All isolates were screened for their anti-inflammatory activity by evaluating their inhibitory effect on NO production in LPS-stimulated RAW 264.7 macrophage cells. Compounds 1, 2, 4, and 5 showed potent inhibitory effects on LPS-induced NO production with IC50 values ranging from 18.88 to 31.77 mu M.

Nine undescribed abietane diterpenoids (1-9) and eleven known abietane analogs (10-20) were isolated from Callicarpa bodinieri. Their structures were characterized by interpreting spectroscopic data, X-ray crystallog-raphy, and ECD analysis. The anti-inflammatory activities of these compounds were tested by evaluation of their inhibitory effect on NO production by lipopolysaccharide in RAW 264.7 macrophages, and compounds 3 and 8 exhibited potent anti-inflammatory activities with IC50 values of 36.35 & PLUSMN; 1.12 and 37.21 & PLUSMN; 0.92 & mu;M. The western blotting studies demonstrated that compound 3 inhibited the expression of nitric oxide synthase and p65 that involved in the NF-& kappa;B pathway.

Class II lanthipeptide synthetases (LanMs) are relatively promiscuous to core peptide variations. Previous studies have shown that different LanMs catalyze identical reactions on the same core sequence fused to their respective cognate leaders. We characterized a new LanM enzyme from Microcystis aeruginosa NIES-88, MalM, and demonstrated that MalM and ProcM exhibited disparate dehydration and cyclization patterns on identical core peptides. Our study provided new insights into the regioselectivity of LanMs and showcased an appropriate strategy for lanthipeptide structural diversity engineering.

A phytochemical investigation of the EtOH extract of the roots of Rheum palmatum L. was performed, leading to the isolation of 3 new acylglycosides (1-3) and 19 previously reported compounds, including 4 cinnamoyl glucosides (4-7) and 15 anthraquinones (8-22). Their structures were elucidated using nuclear magnetic resonance, infrared, ultraviolet and high-resolution electrospray ionization mass spectra and X-ray diffraction data. The biological activities of compounds 2, 4-9, and 11-13, including their lymphocyte activation gene 3 (LAG3)/ major histocompatibility complex class II (MHC II) and LAG3/fibrinogen-like protein 1 (FGL1) binding inhibition activities, were evaluated. Among the isolates, compound 7 exhibited clear inhibitory activity against the LAG3/ FGL1 interaction with an IC50 of 7.89 mu M, meanwhile compound 6 inhibited the LAG3/MHC II interaction with an IC50 of 6.00 mu M.

Thioamitides are apoptosis-inducing ribosomally synthesized and post-translationally modified peptides (RiPPs) with substantial post-translational modifications (PTMs), whose biosynthetic details remain elusive. We reconstituted their key PTMs through in vitro enzymatic reactions and gene coexpressions in E. coli and rigorously demonstrated the order of those modifications. Notably, thioamitide biosynthesis involves N- to C-terminal thioamidations and employs both leader-dependent and leader-independent reactions followed by leader removal by successive degradation. Our study provides a comprehensive overview of thioamitide biosynthesis and lays the foundation for thioamitide engineering in E. coli.

Four new diterpenoids (1-4), and 18 known ones were isolated from the roots of Euphorbia fischeriana Steud (Euphorbiaceae). These diterpenoids shared six skeleton types, including ent-atisane, kaurane, 3,4-secokaurane, lathyrane, 4,5-secoatisane and ingenane diterpenoids. The structures of the new diterpenoids were characterized by a combination of spectroscopic techniques and X-ray crystallography. Moreover, biological evaluation revealed that compounds (16S*)-atisan-3β,16,17-triol (7), (16S*)-3β,16,17,18-tetrahydroxykaurane (12) and (16S*)-3α-hydroxykauran-16,17-acetonide (15) showed inhibitory activity against the interferon regulatory factors (IRFs) involved pathway.

Isolation and identification of natural products from plants is an essential approach for discovering drug candidates. Herein we report the characterization of three sesquiterpene lactones from a new genus Shangwua, e.g. onopordopicrin (ONP), C2, and C3, and evaluation of their pharmacological functions in interfering cellular redox signaling. Compared to C2 and C3, ONP shows the most potency in killing cancer cells. Further experiments demonstrate that ONP robustly inhibits thioredoxin reductase (TrxR), which leads to perturbation of cellular redox homeostasis with the favor of oxidative stress. Knockdown of the TrxR sensitizes cells to the ONP treatment while overexpression of the enzyme reduces the potency of ONP, underpinning the correlation of TrxR inhibition to the cytotoxicity of ONP. The discovery of ONP expands the library of the natural TrxR inhibitors, and the disclosure of the action mechanism of ONP provides a foundation for the further development of ONP as an anticancer agent.

A phytochemical study led to the isolation of 25 diterpenoid alkaloids from Aconitum sinomontanum, of which six were described for the first time. Among them compounds 1-3 are anhydrolycoctonine derivatives, rare rearranged aconitine-type C-19-diterpenoid alkaloids. To our best knowledge, less than ten of this type of alkaloids were isolated just from the genus Aconitum. The structures of these unreported compounds were elucidated by extensive analysis of NMR spectroscopic data and X-ray diffraction. The biological activities of compounds 1-3, 5-9, and 12-25 were evaluated. Among the tested compounds, compounds 2 and 17 showed potent inhibitory effect on the capsaicin (selective TRPV1 agonist) mediated activation of transient receptor potential vanilloid 1 (TRPV1) channels expressed in HEK-293 cells with inhibition rate of 31.78% and 30.94% at the concentration of 10 mu M. Compounds 1-3, 5-9, 13, and 18-25 exhibited weak cytotoxic activity against human tumor cell lines NCI-H226 and MDA-MB-231 with inhibition rate over 10% at the concentration of 10 mu M. Compound 16 showed most inhibitory effect on the expression of Nrf2 (NF-E2-related factor-2)-regulated gene with inhibition rate of 25% at the concentration of 20 mu M.

Bioactivity guided the isolation of extracts from the aerial parts Scutellaria barbata D. Don to discover neo-clerodane diterpenoids with potent phytotoxic activity. Of the 34 isolates, 13 neo-clerodane diterpenoids were described for the first time. The structures of these undescribed compounds were elucidated by extensive analysis of NMR spectroscopic data, and the absolute configurations of scutebarbolides A and L and scutebata W were determined by X-ray diffraction. The phytotoxic activity of all compounds against the growth of the roots and shoots of L. perenne and L. sativa seedlings were first reported, and some compounds showed considerable inhibitory effects, especially scutebarbolide K, whose inhibition rates were higher than those of the positive control at concentrations ranging from 25 to 200 μg/mL. When L. perenne and L. sativa seedlings were treated at a concentration of 200 μg/mL, scutebarbolide K caused wilting symptoms on and finally death of these two tested plant seedlings. In addition, the structure-activity relationships of these neo-clerodane diterpenoids were also discussed.

Ten highly oxygenated diterpenoids (nine undescribed ones) were isolated from the aerial parts of Leonurus japonicus Houtt. 14,15-Dinor-labd-5,8-dien-3,13-dione was a 14,15-dinor-labdane diterpenoid possessing a C18 skeleton. 7β,9α-Dihydroxy-6-oxo-labd-13-en-15,16-amide represented a rare example of labdane diterpenoid featuring an α,β-unsaturated-γ-lactam moiety. The structures of all compounds were elucidated using spectroscopic data analyses and comparisons. The effects of these obtained compounds on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 cells were evaluated.(10R*,13R*,15R*)-15,16-Epoxy-6,13-dihydroxy-15-methoxy-labda-5,8-dien-7-one inhibited NO production with an IC50 value of 40.1 μM.

Three new highly modified lanostane triterpenoids schisanchinlactone A-C (1-3), together with six known compounds (4-9) were isolated from the stems and leaves of Schisandra chinensis. Their structures were established by extensive spectroscopic analyses. Compounds 7 and 8 showed significant inhibition of Cdc25A phosphatase with inhibitory rates of 85.5% and 98.1%, respectively, at the concentration of 100 μM.

Phytotoxic natural products with either unique or various structures are one of the most abundant sources for the discovery of potential allelochemicals, natural herbicides, and plant growth regulators. Phytotoxic diterpenoids, a relatively large class of natural products, play an important role in the plant-plant or plant-microorganism interactions. This article argues that the phytotoxic diterpenoids isolated from the plants and microorganisms can either inhibit the seed germination and the growth of plant seedlings or lead to some disease symptoms on the tested plant tissues and plant seedlings.

Heliaquanoid A (1), the first exo-2,4-linked Diels-Alder adduct between a pseudoguaianolide dienophile and a guaianolide diene, and heliaquanoids B-E (2-5), four new 2,4-linked Diels-Alder adducts between a xanthanolide dienophile and a guaianolide diene, were isolated from stems and leaves of Inula helianthus-aquatica. Their structures were determined by NMR spectroscopy, a modified Mosher's method, electronic circular dichroism, and X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate cytotoxic activities against HL-60 cells with IC50 values of 7.5 and 4.9 mu M, respectively.