Structurally diverse triterpenoid alkaloids from Buxus rugulosa.

Four new nortriterpenoid alkaloids, namely buxrugulines E-H (1-4), along with five known ones (5-9), were isolated from the twigs and leaves of Buxus rugulosa. Their structures were identified based on extensive NMR data and MS spectroscopic analyses. Our bioassays revealed that compounds 5, 6 and 8 exhibited potent cytotoxicity in vitro against MCF-7 cell lines, with IC50 values ranging from 6.70 to 11.00 µM, respectively.

Anti-Inflammatory Lindenane Sesquiterpenoid Dimers from the Roots of Sarcandra glabra.

Sarglaroids A-H (1-8), eight new lindenane dimers, and a monomer sarglaroid I (9), along with fourteen known analogues (10-23), were isolated from the roots of Sarcandra glabra. The planar structures and the absolute configurations were elucidated by HR-MS, NMR, ECD calculations, and X-ray diffraction crystallography. Sarglaroid A (1) was identified as a rare 8,9-seco lindenane dimer with a unique 5/5/5 tricyclic system. The biological evaluation showed that compounds 1 and 13 potently inhibited NO production with IC50 values at 19.8 ± 1.06 and 10.7 ± 0.25 µM, respectively, and had no cytotoxicity to RAW264.7 cells. Compound 6 significantly inhibited the LPS-/ATP-induced IL-1ß release by inactivating the NLRP3 inflammasome through inhibiting the initiation and assembly by affecting the K+ efflux. Compounds 2 and 3 inhibited the proliferation of MCF-7 and MDA-MB-231 with IC50 values ranging from 5.4 to 10.2 µM.

d-chiro-Inositol Derivatives with Multidrug Resistance Reversal Activities from the Fruits of Chisocheton siamensis.

Chisosiamols A-K (1-11), 11 new d-chiro-inositol derivatives, along with a known analogue (12) were isolated from the fruits of Chisocheton siamensis. Their planar structures and relative configurations were elucidated by the comprehensive application of spectroscopic methods, especially from the characteristic coupling constants, and 1H-1H COSY spectra. The absolute configurations of the d-chiro-inositol core were determined using the ECD exciton chirality and X-ray diffraction crystallographic analytical methods. This is the first crystallographic data reported for the d-chiro-inositol derivatives. A structural elucidation strategy mainly combining 1H-1H COSY correlations and ECD exciton chirality for determining the structure of d-chiro-inositol derivatives was developed, which also led to the revisions of previously reported structures. Bioactivity evaluation indicated that chisosiamols A, B, and J can reverse multidrug resistance in MCF-7/DOX cells in the IC50 range of 3.4-6.5 µM (RF: 3.6-7.0).

Rare noreudesmane sesquiterpenoids from the fruits of Dysoxylum densiflorum.

Seven rare noreudesmane sesquiterpenoids (dysoxydenones M-S, 1-7), including three 11,12,13-trinoreudesmanes, three 13-noreudesmanes and one spirovetivane-type sesquiterpenoid, along with two known analogues were isolated from the fruits of Dysoxylum densiflorum. The planar structures were elucidated by a combination of 1D, 2D NMR and HRESIMS analyses. Their absolute configurations were determined by combination of single-crystal X-ray diffraction, CD exciton chirality method and ECD calculation. All compounds were screened for anti-inflammatory activity on LPS-induced RAW 264.7 cells and IL-1ß inhibitory activity.

Diverse acyclic diterpene derivatives from Aphanamixis sinensis.

Fifteen diterpene derivatives including seven new ones, sinensisins A-G (1, 2, 4, 7, 10, 14, 15), were obtained from the leaves and twigs of Aphanamixis sinensis. Their structures were elucidated by NMR spectroscopic and ECD data analyses. These diverse carbon skeletons containing meroditerpenoids, acyclic diterpenes, and norditerpenoids biogenetically were derived from chain-like diterpenes. Compounds 3, 5, and 6 showed inhibitory effects of nitric oxide (NO) production in LPS-induced RAW 264.7 cells.

Inhibition of the P2X7/NLRP3 Inflammasome Signaling Pathway by Deacetylgedunin from Toona sinensis.

Limonoids are considered the effective part in Meliaceae plants that exert anti-inflammatory effects. Gedunin-type limonoids specifically have anti-inflammatory effects. However, the role of gedunin-type limonoids in the inflammatory diseases mediated by NLRP3 inflammasome remains to be explored. We found that deacetylgudunin (DAG), a gedunin-type limonoid from Toona sinensis, had similar anti-inflammatory effects and lower toxicity than gedunin. Further studies showed that DAG down-regulated the NF-κB pathway, inhibited K+ efflux and ROS release, inhibited ASC oligomerization, and significantly weakened the interaction of NLRP3 with ASC and NEK7. Furthermore, DAG could not further inhibit IL-1ß secretion and K+ efflux when combined with the P2X7 inhibitor A438079. In conclusion, our research revealed that DAG exerted an anti-inflammatory effect by inhibiting the P2X7/NLRP3 signaling pathway and enriched the application of gedunin-type limonoids in inflammatory diseases driven by the NLRP3 inflammasome.

A/D-rings-seco limonoids from the fruits of Aglaia edulis and their bioactivities.

Agledulines A-K, eleven previously undescribed limonoids, including eight biogenic A/D-rings-seco limonoid analogs (agledulines A-H), one D-ring-seco limonoid (agleduline I) and two A-ring-seco limonoids with a rare Δ4,28 moiety (agledulines J-K), together with twelve reported limonoids, were isolated from the fruits of Aglaia edulis. Their structures were determined by NMR data, HRESIMS, X-ray diffraction, ECD spectra and the CD exciton chirality method. Observably, the absolute configurations of agleduline A, agleduline C and nymania 2 were unambiguously elucidated by single-crystal X-ray diffraction analyses. The biological evaluation showed that agleduline C exhibited significant cytotoxic activities with IC50 values of 10.05 µM, and 11α-acetoxygedunin showed notable anti-inflammatory activity (IC50: 4.70 µM). In addition, agleduline I and 11α-acetoxygedunin reversed the multidrug resistance with IC50 values of 5.05 and 1.49 µM (RI: 4.64 and 15.77) in the MCF-7/Dox cells.

Lignans with (N, N-diethyl)methyl amino group from Buxus rugulosa.

Buxrugulosides A-E, four lignan glycosides (1-4) and a protocatechuate derivative (5) featuring a rare (N, N-diethyl)methyl amino group at aromatic rings, were obtained from the aerial parts of Buxus rugulosa, which is famous for treating coronary heart disease. Their structures including absolute configurations were elucidated by HRMS, 1D and 2D NMR, and by comparing their CD data with previous reports. Compound 1 was a rare sesquilignan, and all of these compounds were the first example of lignans with (N, N-diethyl)methyl amino group.

Limonoids with Diverse Oxidation Patterns of C-12 Indicating a Complete Ring C-seco Biogenetic Pathway from Munronia unifoliolata.

Munrolins A-Q (1-17), 17 new ring C-seco limonoids with diverse oxidative patterns of C-12, together with nine known analogues (18-26), were isolated from the CH2Cl2 extract of Munronia unifoliolata. The planar structures were elucidated by a combination of 1D and 2D NMR and HR-MS analyses, while the absolute configurations were confirmed by ECD calculations and single-crystal X-ray diffraction. Munrolins A (1) and B (2) were first identified as ring C-seco limonoids with a 12,13-ether bridge moiety. Munrolins C-J (3-10) have a rare reduced primary alcohol fragment, while munrolin Q (17) has an unusual ketal fragment formed by dehydration of C-12/14. These limonoids with diverse alcohol and aldehyde type C11/12 branches may be generated through different degrees of reduction after the Baeyer-Villiger oxidation at the C ring, as key intermediates to supplement the biogenetic pathway of ring C-seco limonoids. Compounds 11, 19, and 26 could reverse the multidrug resistance of MCF-7/doxorubicin cells with reversal fold values of 5.2, 4.5, and 18.3, respectively.

Aglatestine A, a Rearranged Limonoid with a 3/6/6 Tricarbocyclic Framework from the Fruits of Aglaia edulis.

Aglatestine A (1), an unprecedented 3/6/6 tricarbocyclic limonoid framework along with four biogenic A/D-seco limonoid analogues with rare ß-substituents at C-6 (2-5), was discovered from the fruits of Aglaia edulis. The structures of 1-5 along with their absolute configurations were clarified using methods of HRMS(ESI), NMR, electronic circular dichroism, X-ray diffraction crystallography, and quantum chemical calculations. The plausible biogenetic speculation suggested that an electrophilic cyclization between C-1 carbocation from acetolysis and electron-rich C-5 from enolization of C═O of 2 may play a key role. The biological evaluation showed that 5 exhibited anti-inflammatory activity indicated by inhibiting NO release in LPS-activated RAW 264.7 macrophages (IC50: 35.72 ± 1.96 µM).

Chisosiamens A-E, five new ring-intact limonoids with isomerized furan ring from the fruit of Chisocheton siamensis.

Five new ring-intact limonoids with isomerized furan ring, chisosiamens A-E (1-5), along with four known compounds (6-9) were isolated from the fruit of Chisocheton siamensis Craib. Their structures were elucidated based on 1D and 2D NMR spectroscopic data, HRESIMS, circular dichroism, and exciton chirality method. The biological activities screening showed that new limonoid 5 exhibited significant NO inhibitory activity in LPS-activated RAW 264.7 macrophages (IC50: 10.13 ± 1.40 µM) and 1, 2, 5, and 9 effectively reversed the resistance in MCF-7/DOX cells with the range IC50 values of 10.20-15.06 µM (RI: 4.05-5.98).

Shizukaol A exerts anti-inflammatory effect by regulating HMGB1/Nrf2/HO-1 pathway.

BACKGROUND: Sarcandra glabra (Thunb.) Makino (Chloranthaceae) has a long history of being used in Traditional Chinese medicines (TCMs) to treat painful joints, fractures, arthritis, and other diseases caused by inflammation. It has been reported that lindenane-type sesquiterpenoid dimers are main anti-inflammatory ingredient of S. glabra. Meanwhile, shizukaol A, the precursor of these sesquiterpene dimers, possesses a good inhibitory effect on nitric oxide (NO) in our previous study. But its anti-inflammatory mechanism is still unclear. PURPOSE: This study aimed to explore the possible anti-inflammatory mechanism and potential targets of shizukaol A in lipopolysaccharide (LPS)-induced RAW 264.7 cells. METHODS: The release of NO and inflammatory cytokines in LPS-stimulated RAW 264.7 cells were measured by Griess reagent and ELISA, respectively. The relevant proteins including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB) p65, High mobility group box 1 (HMGB1) were detected by western blot. Nuclear translocation of p65, HMGB1 and nuclear factor E2-related factor 2 (Nrf2) were examined by immunofluorescence. The level of reactive oxygen species (ROS) was tested by flow cytometry. The target of shizukaol A was investigated by molecular docking and Drug Affinity Responsive Target Stability (DARTS). RESULTS: Shizukaol A had a good inhibitory effect on NO with half maximal inhibitory concentration (IC50) of 13.79 ± 1.11 µM. Shizukaol A could down-regulate the expression of iNOS and COX-2. Further studies demonstrated that shizukaol A can significantly inhibit phosphorylation and nuclear translocation of NF-κB. Meanwhile, shizukaol A decreased the level of ROS and enhanced the expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Furthermore, shizukaol A up-regulated the expression of Nrf2 and its nuclear translocation. More importantly, shizukaol A could inhibit activation of HMGB1 by targeting HMGB1. CONCLUSION: Shizukaol A inhibited inflammation by targeting HMGB1 to regulate the Nrf2/HO-1 signaling pathway. Thus, shizukaol A may be an attractive therapeutic candidate for inflammatory diseases.

Stigmastane-type steroid saponins from the leaves of Vernonia amygdalina Del.

Vernoramyosides A-F (1-6), six new Δ7,9(11) stigmastane-type steroid saponins, along with four known analogues (7-10) were isolated from the leaves of Vernonia amygdalina Delile (Compositae). Their structures were determined by the combination of NMR, ECD and HR-ESI-MS data. These compounds all possessed highly oxidized side chain and a γ-lactam or α,ß-unsaturated five-membered lactone ring. All isolates were screened for their activities in reversing resistance in MCF/DOX cells.