Isolation and biomimetic synthesis of phenylpropionyl phenylethylamines from Chloranthus henryi.

In this study, ten phenylpropionyl phenylethylamines, including five previously undescribed ones (1a/b, 2a/b, and 3), five known analogues (4-8), and two established phenylpropanoids precursors (9, 10) were isolated from the aerial parts of Chloranthus henryi Hemsl. Their structures, including absolute configurations, were determined by high-resolution mass spectrometry, enantio-separation, electronic circular dichroism calculation, and single crystal diffraction. Compounds 1a and 1b were the first examples of natural hetero-[2 + 2] cycloaddition products between phenylpropionyl phenylethylamine and phenylpropene. The plausible hetero-[2 + 2] biosynthesis pathway was confirmed by a photocatalytic biomimetic synthesis in eight steps, which also led to the production of three other potential natural homo-[2 + 2] adducts (1'a/b, 2', and 3'). Bioactivity screening indicated that these adducts bear medium inhibitory activity on nitric oxide generation, with IC50 values of 6-35 µM in RAW 264.7 macrophages.

1H NMR guided isolation of 3-arylisoquinoline alkaloids from Hypecoum erectum L. and their anti-inflammation activity.

Nine 3-arylisoquinoline alkaloids including five undescribed ones, hypectumines A-E (1-5), were isolated from the whole herb of Hypecoum erectum L. with the guidance of 1H-NMR. Their structures were established by a combination of 1D, 2D NMR, and HRESIMS spectrometry. Among them, hypectumines A and B possessed rare urea moieties while hypectumines C and D were characterized by 3-(methylamino)propanoic acid scaffolds. Biological assay demonstrated that alkaloids hypectumine B and 2,3-dimethoxy-N-formylcorydamine had anti-inflammatory effects by inhibiting NO production on LPS-induced RAW264.7 cells with IC50 values of 24.4 and 44.2 µM, respectively. Furthermore, hypectumine B could reduce the expression of pro-inflammatory cytokines TNF-α and IL-6, suggesting it might be a potential candidate for treating inflammatory disease.

Chemical Constituents from the Heartwood of Solanum Verbascifolium L. And Their Anti-Inflammatory Activities Combined Network Pharmacology.

Phytochemical studies on 95 % ethanol extract of the heartwood of Solanum verbascifolium L. resulted in the isolation of one new amide derivative (1), and 21 known phenylpropanoids compounds. The structures were characterized by spectral analysis and high-resolution mass spectrometric analysis. The anti-inflammatory activity of amide compounds 1-4 and 6-9 by investigating their impact on the release of nitric oxide (NO) in MH-S cells. Our findings unveiled significant inhibitory effects on NO secretion. Compound 1 exhibited robust dose-dependent suppression, with pronounced inhibition observed at both 20 µM (P<0.01) and 40 µM (P<0.01). Furthermore, compound 9 demonstrated noteworthy inhibitory effects at 40 µM (P<0.01). Similarly, compounds 3 and 4 displayed substantial inhibition of NO secretion at the same concentration, although the significance level was slightly lower (P<0.05). It is expected that there is a substantial association between the anti-inflammatory activities of amides and their targets, specifically PTGS2, by combining network pharmacology and molecular docking techniques. This discovery emphasizes amides' potential as an interesting subject for additional study in the realm of anti-inflammatory medications.

Chemical Composition of Artemisia Scoparia and Their Bioactivities.

Three undescribed sesquiterpenes (1-3), two enantiomeric pairs of monoterpenes (4a/4b-5a/5b), one alkyne (6), two known alkynes (7-8) and eight known coumarins (9-16) were isolated from the aerial parts extracts of Artemisia scoparia. The structures of these compounds were fully elucidated by their 1D and 2D NMR, HRESIMS spectral data analyses, and comparison with literature. The absolute configurations of compounds were determined by single-crystal X-ray crystallography (1), a comparison of experimental and calculated electronic circular dichroism (ECD) data (2-6). 15 showed moderate inhibitory activity with the NO release in LPS-induced RAW264.7 cells. 9-16 showed varying degrees of promoting melanogenesis and tyrosinase activity in B16 cells.

Undescribed Lignanamide and Flavone C-Glucoside Isolated from the Aerial Parts of Piper Samentosum with NO Production Inhibitory Activity in LPS Activated RAW 264.7†Cells.

In this study, two undescribed compounds (1 and 2), together with eight known compounds (3-10) were isolated from the aerial parts of Piper samentosum by various chromatography methods. Their chemical structures were determined to be 7'''-oxolyciumamide N (1), vitexin 2''-O-ß-D-(6'''-feruloyl)-glucopyranoside (2), 1,2-dihydro-6,8-dimethoxy-7-hydroxy-1-(3,4-dihydroxyphenyl)-N1,N2-bis-[2-(-hydroxyphenyl)ethyl]-2,3-napthalene dicarboamide (3), vitexin 6''-O-ß-D-glucopyranoside (4), vitexin 2''-O-α-L-rhamnopyranoside (5), methyl 2-hydroxybenzoate-2-O-ß-D-apiofuranosyl-(1→2)-O-ß-D-glucopyranoside (6), ficuside G (7), methyl 2-O-ß-D-glucopyranosylbenzoate (8), methyl 2,5-dihydroxybenzoate-5-O-ß-D-glucopyranoside (9), and 3,7-dimethyloct-1-ene-3,6,7-triol 6-O-ß-D-glucopyranoside (10) by spectroscopic data analysis including HR-ESI-MS, 1D-, and 2D-NMR spectra. Compounds 1-5 inhibited nitric oxide production in LPS-stimulated RAW264.7 macrophages with the IC50 values of 27.62, 74.03, 38.54, 70.39, and 44.95 µM, respectively. The NMR data of 9 were firstly reported herein.

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.

Discovery of 6-Acylamino/Sulfonamido Benzoxazolone with IL-6 Inhibitory Activity as Promising Therapeutic Agents for Ulcerative Colitis.

Ulcerative colitis has been widely concerned for its persistent upward trend, and the sustained overproduction of pro-inflammatory cytokines such as IL-6 remains a crucial factor in the development of UC. Therefore, the identification of new effective drugs to block inflammatory responses is an urgent and viable therapeutic strategy for UC. In our research, twenty-three 6-acylamino/sulfonamido benzoxazolone derivatives were synthesized, characterized, and evaluated for anti-inflammatory activity against NO and IL-6 production in LPS-induced RAW264.7 cells. The results demonstrated that most of the target compounds were capable of reducing the overexpression of NO and IL-6 to a certain degree. For the most active compounds 3i, 3j and 3 l, the inhibitory activities were superior or equivalent to those of the positive drug celecoxib with a dose-dependent relationship. Furthermore, animal experiments revealed that active derivatives 3i, 3j and 3 l exhibited definitive therapeutical effect on DSS induced ulcerative colitis in mice by mitigating weight loss and DAI score while decreasing levels of pro-inflammatory cytokines such as IL-6 and IFN-γ, simultaneously increasing production of anti-inflammatory cytokines IL-10. In addition, compounds 3i, 3j and 3 l could also inhibit the oxidative stress to alleviate ulcerative colitis by decreasing MDA and MPO levels. These finding demonstrated that compounds 3i, 3j and 3 l hold significant potential as novel therapeutic agents for ulcerative colitis.

Isolation and characterization of dihydrohomoisoflavonoids from Portulaca oleracea L.

Eight pairs of dihydrohomoisoflavonoids (1-8), including four pairs of enantiomeric aglycones [(R,S)-portulacanones B (1) and C (2) and (R,S)-oleracones C (3) and Q (4)] and four pairs of epimeric glycosides [portulacasides A-D and epiportulacasides A-D (5-8)], were obtained from Portulaca oleracea L. Among them, (R,S)-oleracone Q (4) and four pairs of epimeric glycosides (5-8) were reported for the first time. The 50% EtOH fraction from the 70% EtOH extract prevented HepG2 human liver cancer cell damage induced by N-acetyl-p-aminophenol (APAP), and the cell survival rate was 62.3%. Portulacaside B (6a), which was isolated from the 50% EtOH fraction, exhibited hepatoprotective and anti-inflammatory effects. The compound increased the survival rate of APAP-damaged HepG2 human liver cancer cells from 40.0% to 51.2% and reduced nitric oxide production in RAW 264.7 macrophages, resulting in an inhibitory rate of 46.8%.

The basic chemical substances of total alkaloids of Uncaria rhynchophylla and their anti-neuroinflammatory activities.

To clarify the chemical basis of the total alkaloids of Uncaria rhynchophylla, HPLC-VWD chromatogram of total alkaloids was established. Under its guidance, modern chromatographic and spectroscopic techniques were used to track, isolate and identify the representative principal components. As a result, one new monoterpenoid indole alkaloid, 3S,15S-N4-methoxymethyl-geissoschizine methyl ether (1), together with 20 known alkaloids (2-21), and 5 other known compounds (22-26) were obtained. Meanwhile, sixteen characteristic peaks were identified from the total alkaloids using HPLC analysis. Then, the anti-neuroinflammatory effect of compounds 1-21 was assessed through inhibiting nitric ---oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Among them, compounds 1, 3, 7, 8, 11, 12, 19 and 21 showed potent inhibitory activities with IC50 values of 5.87-76.78 µM.

Anti-Inflammatory and Antioxidant Effects of Rosmarinic Acid Trimetallic (Cu0.5Zn0.5Fe2O4) Nanoparticles.

Newly, green metallic-nanoparticles (NPs) have received scientists' interest due to their wide variable medicinal applications owned to their economical synthesis and biologically compatible nature. In this study, we used rosmarinic acid (RosA) to prepare Cu0.5Zn0.5FeO4 NPs and later encapsulated them using PEG polymer. Characterization of NPs was done using the XRD method and SEM imaging. Further, we explored the encapsulated NPs for anti-inflammatory properties by downregulating the expression of pro-inflammatory cytokines mRNA in LPS-stimulated Raw 264.7 cells. Besides, employing DPPH, NO and ABTS radical scavenging assays to examine the antioxidant activity of the synthesized Cu0.5Zn0.5FeO4 NPs. Cu0.5Zn0.5FeO4 NPs revealed moderate antioxidant activity by scavenging DPPH and nitric oxide. We demonstrated that the NPs showed high potential anti-inflammatory activity by suppressing the mRNA and protein levels of pro-inflammatory cytokines in a dose-dependent manner, in LPS-induced Raw 264.7 cells. To our best knowledge, this is the first report where RosA was found to be a suitable phyto source for the green synthesis of Cu0.5Zn0.5FeO4 NPs and their in vitro anti-inflammatory and antioxidant effects. Taken together, our findings suggest that the RosA is a green resource for the eco-friendly synthesis of Cu0.5Zn0.5FeO4/PEG NPs, which further can be employed as a novel anti-inflammatory therapeutic agent.

Anti-inflammatory ent-cleistanthane-type diterpenoids from Phyllanthus rheophyticus.

A bioactivity-guided isolation from the aerial parts of Phyllanthus rheophyticus obtained 17 undescribed ent-cleistanthane-type diterpenoids, namely phyllarheophols A-Q, as well as 12 known analogs. Their structures were characterized by a combination of spectroscopic data interpretation, single-crystal X-ray diffraction and ECD analysis. The anti-inflammatory activities of these compounds were evaluated by measuring their inhibitory effects on NO production in LPS-stimulated RAW264.7 macrophages, and their preliminary structure-activity relationships were also discussed. Further study showed that promising compounds phyllarheophol D and phyacioid B significantly suppressed the expressions of cytokines and nitric oxide synthase through the NF-κB signaling pathway.

Tricholosterols A-D, four new ergosterol derivatives from the mushroom Tricholoma terreum.

Four ergosterol derivatives, named tricholosterols A-D (1-4), have been isolated from the fruiting bodies of Tricholoma terreum. Their chemical structures have been determined using a combination of spectroscopic analysis as well as computational methods. Compound 1 possesses a rare D-ring opening ergosterol skeleton, while compounds 2-4 are rare degraded ergosterols. Compounds 1 and 4 exhibited moderate inhibitory activity against NO production with IC50 values of 27.6 and 31.8 µM, respectively. This is the first report of steroids from T. terreum.

Targeted Isolation of Anti-inflammatory Lignans from Justicia aequilabris by Molecular Networking Approach.

Herein, the isolation of secondary metabolites from the aerial parts of Justicia aequilabris guided by HPLC-MSn and molecular networking analyses is reported. Twenty-two known compounds were dereplicated. Three new lignans (aequilabrines A-C (1-3)) and three known compounds (lariciresinol-4'-O-ß-glucose (4), roseoside (5), and allantoin (6)) were obtained. The anti-inflammatory activity of compounds 1-3 was evaluated in vitro by inhibiting the nitric oxide production (NO) and pro-inflammatory activity on the cytokine IL-1ß. Compounds 2 and 3 showed significant inhibitory activity against NO production, with IC50 values of 9.1 and 7.3 µM, respectively. The maximum inhibition of IL-1ß production was 23.5% (1), 27.3% (2), and 32.5% (3).

Discovery of novel paeonol-based derivatives against skin inflammation in vitro and in vivo.

T-LAK-cell-originated protein kinase (TOPK), a novel member of the mitogen-activated protein kinase family, is considered an effective therapeutic target for skin inflammation. In this study, a series (A - D) of paeonol derivatives was designed and synthesised using a fragment growing approach, and their anti-inflammatory activities against lipopolysaccharide (LPS)-induced nitric oxide production in RAW264.7 cells were tested. Among them, compound B12 yielded the best results (IC50 = 2.14 µM) with low toxicity (IC50 > 50 µM). Preliminary mechanistic studies indicated that this compound could inhibit the TOPK-p38/JNK signalling pathway and phosphorylate downstream related proteins. A murine psoriasis-like skin inflammation model was used to determine its therapeutic effect.

Synthesis of lathyrane diterpenoid nitrogen-containing heterocyclic derivatives and evaluation of their anti-inflammatory activities.

As our ongoing work on lathyrane diterpenoid derivatization, three series of lathyrane diterpenoid derivatives were designed and synthesized based combination principles, including pyrazole, thiazole and furoxan moieties. Biological evaluation indicated that compound 23d exhibited excellently inhibitory activity on LPS-induced NO production in RAW264.7 cells (IC50 = 0.38 ± 0.18 µM). The preliminary structure-activity relationships (SARs) suggested that phenylsulfonyl substituted furoxan moiety had the strongest ability to improve anti-inflammatory activity of lathyrane diterpenoids. Furthermore, compound 23d significantly reduced the level of ROS. Its molecular mechanism was related to inhibiting the transcriptional activation of Nrf2/HO-1 pathway. Based on these considerations, 23d might be a promising anti-inflammatory agent, which is noteworthy for further exploration.

Rare isotachin-derived from the Dasymaschalon rostratum fungus Penicillium tanzanicum ZY-5.

Four rare isotachin-derived, isotachins E-H (1-4), together with two known biogenetically related isotachin derivatives (5 and 6) were isolated from the solid rice fermentation of a fungus Penicillium tanzanicum ZY-5 obtained from a medicinal plant Dasymaschalon rostratum collected from the Changjiang County, Hainan Province, China. Their structures were elucidated using comprehensive spectroscopic methods. The single-crystal X-ray diffraction of compound 5 was determined. Compounds 1-4 have a trans-3-(methylthio)-acrylic acid fragment, which are rare in nature. The inhibitory activities of all compounds against the nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro were evaluated.

Characterization and immunomodulatory effect of an alkali-extracted galactomannan from Morchella esculenta.

In our continuous exploration for bioactive polysaccharides, a novel polysaccharide FMP-2 was isolated and purified from the fruiting bodies of Morchella esculenta by alkali-assisted extraction. FMP-2 had an average molecular weight of 1.09 × 106 Da and contained mannose, glucuronic acid, glucose, galactose, and arabinose in a molar ratio of 4.10:0.22:1.00:5.75:0.44. The backbone of FMP-2 mainly consisted of 1,2-α-D-Galp, 1,6-α-D-Galp, and 1,4-α-D-Manp, with branches of 1,4,6-α-D-Manp and 1,2,6-α-D-Galp. FMP-2 can stimulate phagocytosis and promote the secretion of NO, ROS, and cytokines like IL-6, IL-1ß, and TNF-α in RAW264.7 cells ranging from 25 to 400 µg/mL. FMP-2 had great repairing effect on the immune injury of zebrafish induced by chloramphenicol. The phagocytosis ability of zebrafish macrophages and the proliferation of neutrophils can be greatly enhanced by polysaccharide FMP-2 with concentrations from 50 to 200 µg/mL. These findings suggest that FMP-2 might be used as a potential immunomodulator in the food and pharmaceutical industries.

Microbial transformation and inhibitory effect assessment of uvaol derivates against LPS and HMGB1 induced NO production in RAW264.7 macrophages.

For the discovery of new pentacyclic triterpenes as a potential anti-inflammatory agent, microbial transformation of uvaol by Penicilium griseofulvum CICC 40293 and Streptomyces griseus ATCC 13273 was investigated. Stereoselective hydroxylation and epoxidation reactions were observed in the biotransformation. Moreover, six new metabolites were isolated and structurally elucidated by HR-ESI-MS and NMR spectrum. All the compounds were evaluated upon the inhibitory effects of nitric oxide (NO) release in RAW 264.7 cells induced by lipopolysaccharide (LPS) and high-mobility group box 1 (HMGB1). Among them, compound 3 (13, 28-epoxy-3ß, 7ß, 21ß-trihydroxy-urs-11-ene) with the unique epoxy structure and compound 5 (3ß, 21ß, 24, 28-tetrahydroxy-urs-12-en-30-oic acid), exhibited a considerable inhibitory effect on both models while compound 2 (urs-12-ene-3ß, 7ß, 21ß, 28-tetraol) showed a significant bias in the LPS-induced inflammatory response with IC50 value of 2.22 µM. Therefore, this study could provide some insights on the discovery of the pentacyclic triterpene leads for the treatment of either DAMPs or PAMPs triggered inflammation.

Nitric oxide inhibitory terpenes and its glycosides from Ainsliaea bonatii.

Seven new terpenes and its derivatives classified into a p-menthane glycoside (1), a guaianolide glycoside (2), three eudesmane and its glycosides (3-5), and two mono-terpene derivatives (9 and 10) were isolated from Ainsliaea bonatii, together with three known guaianolides (6-8). Their structures were elucidated by spectroscopic data analysis, and absolute configurations were determined by DP4+ probability analysis via calculated 13C NMR data of isomers. Compounds 6 and 9 showed nitric oxide (NO) inhibitory effects in LPS-induced RAW 264.7 macrophage cells with IC50 values of 9.3 and 10.6 µM, respectively.

NO-HDAC dual inhibitors.

HDAC inhibitors and NO donors have both demonstrated independently broad therapeutic potential in a variety of diseases. Borretto et al. presented the topic of NO-HDAC dual inhibitors for the first time in 2013 as an attractive new topic. Here we collected the general structure of all synthesized NO-HDAC dual inhibitors, lead compounds, synthesis methods and biological features of the most potent dual NO-HDAC inhibitor in each category with the intention of assisting in the synthesis and optimization of new drug-like compounds for diverse diseases. Based on studies done so far, NO-HDAC dual inhibitors have displayed satisfactory results against wound healing (3), heart hypertrophy (3), inflammatory, cardiovascular, neuromuscular illnesses (11a-11e) and cancer (6a-6o, 9a-9d, 10a-10d, 16 and 17). NO-HDAC dual inhibitors can have high therapeutic potential for various diseases due to their new properties, NO properties, HDAC inhibitor properties and also due to the effects of NO on HDAC enzymes.