Synthesis and in†vitro Anti-Inflammatory Activity of Novel Dendrobine Amide/Sulfonamide Derivatives.

A traditional Chinese medicine ingredient, dendrobine, has been demonstrated to have anti-inflammatory properties. However, due to its poor anti-inflammatory properties, its clinical use is limited. Consequently, we have designed and synthesized 32 new amide/sulfonamide dendrobine derivatives and screened their anti-inflammatory activities in vitro. Experiments showed that nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW264.7 cells was strongly reduced by derivative 14, with an IC50 of 2.96 µM. Western blot research revealed that 14 decreased the concentration-dependent expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (INOS). Molecular docking was used to predict the binding of the inflammation-associated proteins COX-2 and INOS to compound 14.

New clerodane diterpenoids from Callicarpa pseudorubella and their antitumor proliferative activity.

Six previously undescribed clerodane diterpenes, cardorubellas A-F (1-6), along with seven known ones (7-13), were isolated from the aerial parts of Callicarpa pseudorubella. Their chemical structures were established by analysis of 1D and 2D NMR, HR-ESI-MS, X-ray diffraction, and electronic circular dichroism (ECD) data. Notably, cardorubella B (2) represented the first examples of naturally occurring succinic anhydride-containing clerodane diterpenes derivatives. The anti-proliferative activities of these compounds were assessed. Remarkably, compound 2 exhibited comparable inhibitory activity against HEL cell lines, surpassing the positive control with an IC50 value of 14.01 ± 0.77 µM, compared to 17.02 ± 4.70 µM for 5-fluorouracil.

Structurally Diverse Coumarins from Peucedanum praeruptorum and their Anti-Inflammatory Activities via NF-κB Signaling Pathway.

The phytochemical study of Peucedanum praeruptorum led to the isolation of twenty-five coumarins (1-25). Of which, (±) praeruptol A (±1), one pair of previous undescribed seco-coumarin enantiomers were obtained. Their structures were established according to HR-ESI-MS, NMR, X-ray single crystal diffraction analysis, as well as ECD calculation. All compounds were tested for anti-inflammatory activity in the RAW264.7 macrophage model, and eight compounds (7-10, and 13-16) exhibited significant inhibitory effects with IC50 values ranging from 9.48 to 34.66 µM. Among them, compound 7 showed the strongest inhibitory effect, which significantly suppressed the production of IL-6, IL-1ß, and TNF-α, as well as iNOS and COX-2 in a concentration-dependent manner. Further investigated results showed that compound 7 exerted an anti-inflammatory effect via the NF-κB signaling pathway.

Limonoids from the Branches and Leaves of Aglaia lawii and Their Cytotoxic Activities.

Three undescribed limonoids (1-3), named aglaians G-I, and one new natural product azedaralide (4), together with nine known analogues (5-13) were isolated from the branches and leaves of Aglaia lawii by RP C18 column, silica gel column, Sephadex LH-20 column chromatography and preparative HPLC. The structures of the new compounds were elucidated by IR, HRESIMS, 1D, 2D NMR, electronic circular dichroism (ECD) calculations and X-ray crystallography diffraction analysis. The results of bioassay showed that the compound 12 exhibited potential inhibitory activity against six human tumor cell lines (MDA-MB-231, MCF-7, Ln-cap, A549, HeLa and HepG-2) with IC50 values as 8.0-18.6 µM.

Unusual triterpenoids and steroids from Cipadessa baccifera and their biological activities.

Five undescribed triterpenoids and steroids (1-5), as well as ten known compounds, were purified from the branches and leaves of Cipadessa baccifera. Notably, 1 and 2 are rare cipadesin-type limonoids with an unusual 8,30-epoxide ring and 1,8-ether linkage, respectively. Compound 5 possessed pregnane steroid skeleton with an uncommon 5/6/6/6/5-fused ring system. Their structures were constructed by extensive spectroscopic analysis (NMR, IR, UV, and HRESIMS), and their absolute configurations were confirmed by ECD calculations and quantum chemical calculations. All the isolates were in vitro assayed for their antimicrobial potentials against 6 pathogenic microorganisms and antiproliferation activities against five human cancer cell lines. As a result, compounds 5, 12, 13, and 14 exhibited moderate antibacterial activities (MIC: 25-50 µg/mL). Moreover, 5 showed cytotoxicity against five cancer cell lines with IC50 values ranging from 8.0 to 19.9 µM.

Design, Synthesis, anti-inflammatory activity Evaluation, preliminary exploration of the Mechanism, molecule Docking, and structure-activity relationship analysis of batatasin III analogs.

Most clinical drugs used to treat inflammation have serious gastrointestinal, renal, and cardiovascular side effects during long-term treatment. The development of new anti-inflammatory agents from natural products and their derivatives is a powerful approach to overcome these adverse effects. Batatasin III, a bibenzyl natural product, has been found to have anti-inflammatory activity. Compared with other anti-inflammatory agents, batatasin III has a simple and unique structure. Therefore, batatasin III and its analogs might have the potential to treat inflammation with only mild adverse effects as a new type of anti-inflammatory agent. Herein, we synthesized 26 batatasin III analogs and evaluated the anti-inflammatory activity in vitro. Analog 21 significantly inhibited (p < 0.01) nitric oxide production with an IC50 value of 12.95 µM. Western blot analysis further revealed that 21 reduced iNOS, phosphorylated p65, and ß-catenin expression in a concentration-dependent manner. These results indicated that 21 could be a potential lead compound for developing a drug candidate for ulcerative colitis. Molecular docking analysis showed that p65 might be a potential target of 21 for the treatment of inflammatory disease. In addition, we analyzed the structure-activity relationship of the analogs, which provides a basis for future structural modifications.

Bioactivities of Steroids and Sesquiterpenes from the Branches and Leaves of Aglaia lawii.

Five undescribed steroids and one sesquiterpene, named Aglaians A-F, along with sixteen known analogs, have been isolated from the branches and leaves of Aglaia lawii. Its structure was elucidated by IR, HRESIMS, 1D and 2D NMR, quantum-chemical calculations, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. The cytotoxic and antibacterial activities of six human tumor cell lines were evaluated (MDA-MB-231, MCF-7, Ln-cap, A549, HeLa, and HepG-2), and four strains of bacteria (Bacterium subtilis, Phytophthora cinnamomic, Acrogenic bacterium, and Ralstonia solanacearum). The bioassay results indicated that compounds 3 and 5 exhibited moderate antitumor activity with IC50 values ranging from 16.72 to 36.14 µM. Furthermore, compounds 3-5 possess antibacterial activities against four bacteria with MIC values of 25-100 µM.

Diverse Flavonoids from the Roots of Indigofera stachyodes.

Three new flavonoids, 4'-O-ß-D-glucopyranosyl-2S,3R-3,7-dihydroxy-3'-methoxyflavan (1), (3R)-7,4'-dihydroxy-5,3'-methoxychalcone (2), (3S)-7,2',3'-trihydroxy-6,4'-dimethoxylisoflavan (3), and one new natural occurring product, (3S)-6,2',3'-trihydroxy-7,4'-dimethoxylisoflavan (4), together with eleven known ones (5-15), were isolated from the roots of Indigofera stachyodes. The structures of these compounds were confirmed by UV, IR, MS, and NMR spectroscopic analysis. The absolute configurations of new compounds were elucidated by ECD spectra and chemical method. All the isolated flavonoids were screened for their antioxidant abilities to scavenge DPPH and ABTS+ . As results, compounds 2-4, 10, and 15 exhibited remarkable scavenging activity against both ABTS+ and DPPH, with the IC50 values less than 20 µM. In addition, compounds 1, 6-9, and 13 exhibited potential antioxidant scavenging activities, IC50 values were in the range of 17.96∼85.91 µM.

Synthesis and evaluation of inhibitors of Mycobacterium tuberculosis UGM using bioisosteric replacement.

There is a dearth of tuberculosis (TB) drug development activity as current therapeutic treatments are inadequate due to the appearance of drug-resistant TB. The enzyme UDP-galactopyranose mutase (UGM) is involved in the biosynthesis of galactan which is essential for cell wall integrity and bacterial viability. Its inhibition has thus been featured as profitable strategy for anti-TB drug discovery. In this study, we report on the synthesis of amides derived from rosmarinic acid, their inhibitory effect towards purified UGM using three distinct biochemical assays: FP, HPLC and SPR. The rosmarinic amides generally showed a significantly higher affinity for UGM than the corresponding rosmarinic ester. In particular, compound 5h displayed interesting binding affinity values (Kd = 58 ± 7, 63 ± 9 µM towards KpUGM and MtUGM respectively). Furthermore, a new UGM SPR assay was established and confirmed that 5h binds to UGM with a dissociation constant of 104.8 ± 6.5 µM. Collectively, this study validates the amide bioisosteric strategy which has been successfully implemented to develop UGM inhibitors from rosmarinic acid, providing a substantial basis for further design of novel UGM inhibitors and anti-mycobacterial agents.

Vulgarisin-type diterpenoids from self-heal (Prunella vulgaris) and their neuroprotective effects against ischemia/reperfusion (I/R) via a mitochondria-related pathway.

Self-heal (Prunella vulgaris L.) is a perennial edible plant that is widely distributed across the world and is traditionally consumed as a food additive in soft drink beverages. In this study, to explore the functional components of P. vulgaris, an investigation of its ethanol extracts has been conducted by our group. As a result, twelve (1-12) vulgarisin-type diterpenoids with a special 5/6/4/5-fused ring skeleton, including six new ones (1-6), were obtained. Their structures including the absolute configuration were elucidated based on comprehensive spectroscopic evidence, ECD calculations, as well as single-crystal X-ray diffraction analyses. All the isolates were tested for neuroprotective effects against ischemia/reperfusion (I/R) on primary neuron cells through the oxygen and glucose deprivation and reperfusion (OGD/R) induced injury model. The results showed that all twelve vulgarisin-type diterpenoids possess promising neuroprotective activity at a concentration of 10 µM. Among them, compound 3 can significantly suppress cell apoptosis by regulating Bax/Bcl-2 protein expression and inhibiting cleaved caspase-3 and caspase-9 expression with a western blotting assay. Further research revealed that compound 3 could improve mitochondrial function by inhibiting mitochondrial cytochrome c release, reducing ROS levels, and maintaining the membrane potential. This work firstly reports vulgarisin-type diterpenoids possessing neuroprotective activity. These findings also suggest that daily consumption of P. vulgaris might prevent cerebral disorders via a mitochondria-related pathway.

Bioactive Bibenzyl Enantiomers From the Tubers of Bletilla striata.

Six new bibenzyls (three pairs of enantiomers), bletstrins D-F (1-3), were isolated from the ethyl acetate-soluble (EtOAc) extract of tubers of Bletilla striata (Thunb.) Rchb f. Their structures, including absolute configurations, were determined by 1D/2D NMR spectroscopy, optical rotation value, and experimental electronic circular dichroism (ECD) data analyses, respectively. Compounds 1-3 possess a hydroxyl-substituted chiral center on the aliphatic bibenzyl bridge, which represented the first examples of natural bibenzyl enantiomers from the genus of Bletilla. The antibacterial, antitumor necrosis factor (anti-TNF-α), and neuroprotective effects of the isolates have been evaluated. Compounds 3a and 3b were effective against three Gram-positive bacteria with minimum inhibitory concentrations (MICs) of 52-105 µg/ml. Compounds 2a and 2b exhibited significant inhibitory effects on TNF-α-mediated cytotoxicity in L929 cells with IC50 values of 25.7 ± 2.3 µM and 21.7 ± 1.7 µM, respectively. Subsequently, the possible anti-TNF-α mechanism of 2 was investigated by molecular docking simulation. Furthermore, the neuroprotective activities were tested on the H2O2-induced PC12 cell injury model, and compounds 2b, 3a, and 3b (10 µM) could obviously protect the cells with the cell viabilities of 57.86 ± 2.08%, 64.82 ± 2.84%, and 64.11 ± 2.52%, respectively.

Novel flavonolignans from the roots of Indigofera stachyodes.

Two pairs of new enantiomeric flavonolignans, ±stachyols A and B (±1 and ± 2), along with two novel isoflavanelignans, stachyols C and D (3 and 4) were isolated from the roots of Indigofera stachyodes. Their chemical structures and absolute configurations were determined using nuclear magnetic resonance and comparison of experimental and theoretical electronic circular dichroism (ECD) spectra, as well as quantum chemical calculations. Of those compounds, 1 and 2 represented the first examples of flavonolignans with 5-deoxyflavonoids adduct phenylpropanoids. Moreover, 3 and 4 possess an unprecedented skeleton with isoflavanes adduct phenylpropanoids. The antioxidant activity was evaluated for all compounds in terms of ABTS+ and DPPH bioassays. Compounds 3 and 4 exhibited significant radical-scavenging activity in the ABTS+ assay, with IC50 values of 15.15 and 5.83 µM, respectively.

Cipacinerasins A-K, structurally diverse limonoids from Cipadessa baccifera.

Eleven undescribed limonoids, cipacinerasins A-K, involving of four diverse carbon skeletal types, along with fifteen known analogues, were isolated from the branches and leaves of Cipadessa baccifera. Within them, cipacinerasins A and B feature a rearranged tetrahydropyranyl ring B formed between C-8 and C-30, are unusual miscellaneous-type limonoids. Cipacinerasins E and F are rare trijugin-type limonoids, of which the D-ring δ-lactone is cleaved. Their structures were elucidated on the basis of extensive spectroscopic data (HRESIMS, NMR, UV and IR), electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. All compounds were evaluated in vitro cytotoxicity against five human tumor cell lines (K562, HeLa, PC3, LN-Cap and Hell), and cipacinerasin E showed moderate antitumor activity with IC50 values ranging from 8.0 to 24.8 µM.

New sesquiterpeniod esters form Blumea balsamifera (L.) DC. and their anti-influenza virus activity.

Phytochemical studies led to the isolation of five new sesquiterpeniod esters, named balsamiferine N-R, along with ten known compounds (6-15) from the leaves of Blumea balsamifera (L.) DC. The skeletons of nine known sesquiterpeniods belong to guaiane and eudesmane. The structures of the new compounds including their absolute configurations were elucidated by comprehensive spectroscopic analysis, and quantum-chemical electronic circular dichroism (ECD) calculation. Compounds 3 and 4 showed significant inhibitory effects on influenza A virus (H3N2) with IC50 values of 46.23 µg/mL and 38.49 µg/mL, respectively. It was the first report on the anti-influenza A virus constituents from B. balsamifera.

Profiling alkaloids in Aconitum pendulum N. Busch collected from different elevations of Qinghai province using widely targeted metabolomics.

Aconitum pendulum N. Busch (Ranunculaceae) is rich in alkaloids with anti-inflammatory and analgesic activities. Many studies have focused on the identification or quantification of alkaloid components using low-throughput tests. However, the metabolic differences of plants from environmentally distinct regions remain unclear. The present study profiled alkaloid chemical compounds in the rhizomes of A. pendulum from different regions. A total of 80 chemical compounds were identified using a widely targeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach. Principal component, hierarchical clustering, and orthogonal partial least squares-discriminant analyses of the chemical compounds indicated that the plants from 6 regions clearly separated into distinct groups. A total of 19 compounds contributed the most to the metabolite differences between collection areas and were identified as potential metabolic markers. The anti-inflammatory activities of the A. pendulum extracts were also evaluated and the potential environmental effects on the regulation of metabolite composition and bioactivity were explored. These results improve our understanding of the variation in chemical composition of plants from different regions and will serve as a reference for evaluating the medicinal value of A. pendulum in different environments.

Non-targeted analysis of vulgarisins by using collisional dissociation mass spectrometry for the discovery of analogues from Prunella vulgaris.

Vulgarisins are members of diterpenoids with rare 5/6/4/5 ring skeleton from Prunella vulgaris Linn. (P. vulgaris). Their molecular scaffolds comprise different hydroxylation and degree of esterification. Vulgarisins have attracted many attentions in the fields of food and medicine for their potent bioactivities. Firstly, four reference compounds were analyzed by higher-energy collisional dissociation mass spectrometry (HCD MS/MS) and the fragmentation patterns for molecular scaffold were summarized. And then, a high-performance liquid chromatography/electrospray ionization/high-resolution mass spectrometry (HPLC-ESI-HR-MS) method was adopted to investigate the P. vulgaris extracts. Finally, the proposed analysis results were successfully applied to facilitate the discovery of the vulgarisins analogues from P. vulgaris. For the four reference compounds, the sodium adduct was the predominate ion in full scan. A specific fragmentation pathway of [M+Na]+ ions leads to produce diagnostic ions of vulgarisins at m/z 325 under HCD, which was formed through consecutive-side chains lost. Twenty-three diterpenoids, including 18 vulgarisins analogues, were identified or tentatively characterized in the botanical extracts of P. vulgaris based on their elemental constituents and characteristic fragment ion profiles. Two new vulgarisins analogues in the plant were isolated and their structures were illustrated based on extensive spectroscopic analysis using 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. The HCD MS/MS method, including the profiles of the diagnostic ions induced by characteristic fragmentation, is an effective technique for the discovery of vulgarisins analogues in P. vulgaris. The expected fragmentation pattern knowledge will also facilitate the analysis of other natural products.

C19-diterpenoid alkaloids from the rhizomes of Aconitum pendulum.

Six new C19-aconitine-type diterpenoid alkaloids, pendulumines A-F (1-6), together with six known ones (7-12), were isolated from the rhizomes of Aconitum pendulum. Their structures were elucidated using extensive spectroscopic data analysis, including 1D and 2D NMR, MS, and single-crystal X-ray diffraction analysis. The isolates were also tested for their analgesic activity based on the thermal avoidance response of the roundworm Pirstionchus pacificus, and 9 showed significant biological activity with an EC50 value of 0.08 ± 0.02 mg.mL-1.

Anti-tobacco mosaic virus (TMV) activity of chemical constituents from the seeds of Sophora tonkinensis.

Two new compounds, including one new arylbenzofuran (1) and one new pterocarpanoid (2), along with nine known ones, were isolated from the seeds of Sophora tonkinensis. The structures of the new compounds were elucidated based on a comprehensive spectroscopic data analysis. Compounds 2 and 3 exhibited good anti-tobacco mosaic virus (TMV) activities with the protective inhibition rate of 69.62% and 68.72% respectively, at concentration of 100 µg/ml.

Polycyclic polyprenylated acylphloroglucinol derivatives with neuroprotective effects from Hypericum monogynum.

A new polycyclic polyprenylated acylphloroglucinol (PPAP), hypermonin C (1), along with nine known PPAPs (2-10) were obtained from the leaves and twigs of Hypericum monogynum. The structures of the isolates were determined on the basis of extensive spectroscopic analysis. The neuroprotective effects of the isolates against several chemical-induced injuries in SH-SY5Y and PC12 cells were assessed, and most of the compounds exhibited significant protective effects at 10 µg/ml. Especially, three compounds (1, 3, and 7) showed excellent neuroprotective activity with a cell viability of 92.4% ∼ 95.8% in KCl-induced SH-SY5Y cell injury. Their preliminary structure-activity relationship was also discussed and the configuration of substituent in furohyperforin may be critical for the neuroprotective activity of PPAP derivatives.

Quinolizidine Alkaloids with Antiviral and Insecticidal Activities from the Seeds of Sophora tonkinensis Gagnep.

The discovery of novel, effective, and botanical pesticides is one of the main strategies for modern plant protection and insect pest control. During the search for novel botanical pesticides from natural sources, the seeds of Sophora tonkinensis were systematically investigated to obtain 11 new matrine-type alkaloids (1-11), including one novel matrine-type alkaloid featuring an unprecedented 5/6/6/6 tetracyclic skeleton (1), along with 16 known compounds (12-27). Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, and HRESIMS), ECD calculations, and single-crystal X-ray diffraction. The anti-tobacco mosaic virus (TMV) activity and insecticidal activities against Aphis fabae and Tetranychus urticae of the compounds were also respectively screened using the half-leaf method and spray method. Biological tests indicated that compounds 2, 4, 6, and 26 displayed significant anti-TMV biological activities compared with the positive control ningnanmycin. Compounds 7, 17, and 26 presented moderate activities against A. fabae with LC50 values of 38.29, 18.63, and 23.74 mg/L, respectively. Moreover, compounds 13 and 26 exhibited weak activities against T. urticae.