Design, synthesis and anti-rheumatoid arthritis activity of target TLR4 inhibitors.

A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro, compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC50 values of 1.21 ± 0.09 µM, 0.73 ± 0.05 µM and 0.43 ± 0.03 µM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1ß and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis.

Design, Synthesis, and Anti-Hepatocellular Carcinoma Evaluation of Sesquiterpene Lactone Epimers Trilobolide-6-O-isobutyrate Analogs.

Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives (3-18) were synthesized using epimers 1 and 2 as parent molecules, isolated from Sphagneticola trilobata, and evaluated for their anti-HCC activity. Furthermore, the structures of 4, 6, and 14 were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of 3-18 on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound 10 exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that 10 induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that 10 may possess the properties to be a drug candidate. Thus, 10 may be a promising lead compound for the treatment of HCC.

[Study on anti-inflammatory activity of phenolic acids from Leucas ciliata].

The chemical constituents from Leucas ciliata belonging to Leucas genus in Lamiaceae were systematically explored by silica gel column chromatography, ODS column chromatography, Sephadex LH-20 gel column chromatography, and preparative high performance liquid chromatography, and seventeen phenolic acids were isolated. The chemical structures of the compounds were identified by their physicochemical properties, spectroscopic data, and literature. They were 4-hydroxyphenethyl ethyl succinate(1), 4-hydroxyphenethyl methyl succinate(2), 2-(4-hydroxyphenyl) ethyl acetate(3), p-hydroxyphenylethyl anisate(4), cassia cis-trans diphenylpropanoid(5), p-coumaric acid(6), 3,4-dihydroxybenzenepropionic acid methyl ester(7), caffeic acid(8), trans-p-hydroxyl ethyl cinnamate(9), methyl p-hydroxybenzeneacetate(10), 4-hydroxyphenethyl alcohol(11), syringic acid(12), vanillin(13), protocatechuic acid(14), salicylic acid(15), p-hydroxybenzaldehyde(16), and diorcinol(17). Among them, compound 1 was new, and compounds 2-10, 12, 14, and 16-17 were isolated from the plants belonging to Leucas genus for the first time. All compounds were obtained from L. ciliata for the first time. The anti-inflammatory activity of compounds 1-17 on NO production in lipopolysaccharide(LPS)-induced mouse leukemia cells of monocyte macrophage(RAW264. 7) cells was evaluated. The results showed that compounds 5, 7, and 9 exhibited significant anti-inflammatory activity, with IC50values of(10. 14±0. 36)-(21. 17±0. 11) µmol·L~(-1).

[Two new pinophol derivatives from endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal].

An OSMAC strategy was used to study secondary metabolites and anti-inflammatory activities of the endophytic fungus Penicillium herquei JX4 hosted in Ceriops tagal. The PDB ferment of fungus P. herquei JX4 was isolated, purified, and identified by using silica gel column chromatography, gel column chromatography, octadecylsilyl(ODS) column chromatography, and semi-preparative high-performance liquid chromatography. Two new pinophol derivatives, pinophol H(1) and pinophol I(2) were isolated and identified, and they were evaluated in terms of the inhibitory activities against the nitric oxide(NO) production induced by lipopolysaccharide(LPS) in mouse macrophage RAW264.7 cells. The results showed that compound 1 had significant inhibitory activity on NO production, with an IC_(50) value of 8.12 µmol·L~(-1).

OSMAC strategy integrated with molecular networking discovery peniciacetals A-I, nine new meroterpenoids from the mangrove-derived fungus Penicillium sp. HLLG-122.

Nine new highly oxygenated meroterpenoids, peniciacetals A-I (1-9), along with five known analogues (10-14) were isolated from the mangrove-derived fungus Penicillium sp. HLLG-122 based on the guidance of molecular networking and OSMAC approach. Peniciacetals A-B (1-2) were characterized with a unique 6/6/6/6/5 pentacyclic system possessing an unusual 4,6-dimethyl-2,5-dioxohexahydro-6-carboxy-4H-furo[2,3-b]pyran moiety. Peniciacetals C-D (3-4) possessed an uncommon 3,6-dimethyldihydro-4H-furo[2,3-b]pyran-2,5-dione unit with 6/6/6/5/6 fused pentacyclic skeleton. The structures and absolute configurations of new compounds were elucidated by HR-ESI-MS, 1D and 2D NMR spectroscopic data, X-ray diffraction analysis, and quantum chemical electronic circular dichroism (ECD) calculation. The plausible biosynthetic pathway of 1-9 were also proposed. Compound 14 showed good cytotoxicity against HepG2, MCF-7, HL-60, A549, HCT116 and H929 cell with IC50 values of 6.6, 14.8, 3.2, 5.7, 6.9 and 3.0 µM, respectively. Further research showed that the compound 14 induced necrosis or late apoptosis contributes to the HL-60 cells toxicity.

Rhizoaspergillin A and Rhizoaspergillinol A, including a Unique Orsellinic Acid-Ribose-Pyridazinone-N-Oxide Hybrid, from the Mangrove Endophytic Fungus Aspergillus sp. A1E3.

Two new compounds, named rhizoaspergillin A (1) and rhizoaspergillinol A (2), were isolated from the mangrove endophytic fungus Aspergillus sp. A1E3, associated with the fruit of Rhizophora mucronata, together with averufanin (3). The planar structures and absolute configurations of rhizoaspergillinol A (2) and averufanin (3) were established by extensive NMR investigations and quantum-chemical electronic circular dichroism (ECD) calculations. Most notably, the constitution and absolute configuration of rhizoaspergillin A (1) were unambiguously determined by single-crystal X-ray diffraction analysis of its tri-pivaloyl derivative 4, conducted with Cu Kα radiation, whereas those of averufanin (3) were first clarified by quantum-chemical ECD calculations. Rhizoaspergillin A is the first orsellinic acid-ribose-pyridazinone-N-oxide hybrid containing a unique ß-oxo-2,3-dihydropyridazine 1-oxide moiety, whereas rhizoaspergillinol A (2) and averufanin (3) are sterigmatocystin and anthraquinone derivatives, respectively. From the perspective of biosynthesis, rhizoaspergillin A (1) could be originated from the combined assembly of three building blocks, viz., orsellinic acid, ß-D-ribofuranose, and L-glutamine. It is an unprecedented alkaloid-N-oxide involving biosynthetic pathways of polyketides, pentose, and amino acids. In addition, rhizoaspergillinol A (2) exhibited potent antiproliferative activity against four cancer cell lines. It could dose-dependently induce G2/M phase arrest in HepG2 cells.

Guaiane-Type Sesquiterpenes from the Stems of Fissistigma oldhamii.

Two new guaiane-type sesquiterpenes dysodensiols J and L, one new natural product dysodensiol K together with four known biogenetically related guaiane-type sesquiterpenes were isolated from the stems of Fissistigma oldhamii. Their structures were elucidated by detailed analysis of NMR, HR-ESI-MS, IR and Optical rotations data. Compound 1 contains an uncommon five-membered ether ring. The inhibitory effect of all compounds on the proliferation of primary synovial cells was evaluated. Compound 3 showed inhibitory activity with an IC50 value of 6.8 µM. Compounds 5-7 exhibited moderate inhibitory activity with IC50 values of 23.8, 26.6, and 27.1 µM, respectively.

Four New Polyhydroxy Cyclohexanes from the Stems of Fissistigma tientangense.

Four undescribed polyhydroxy cyclohexanes, fissoxhydrylenes A-D (1-4), together with two known biogenetically related polyhydroxy cyclohexanes (5 and 6) were isolated from the stems of Fissistigma tientangense Tsiang et P. T. Li. Their structures were elucidated by detailed analysis of NMR, HR-ESI-MS, IR, UV and Optical rotations data. The absolute configuration of 1 was confirmed by X-ray crystallographic. The absolute configurations of 2-4 were confirmed by chemical reaction and optical rotations. Compound 4 represent the first example of a no substituent polyhydroxy cyclohexanes from natural products. All isolated compounds were evaluated for their anti-inflammatory activities against the lipopolysaccharide-induced nitric oxide (NO) production in mouse macrophage RAW 264.7 cells in vitro. Compounds 3 and 4 showed inhibitory activities with the IC50 values of 16.63±0.06 µM and 14.38±0.08 µM, respectively.

Three new long-chain polyenes from the mangrove-derived fungus Penicillium herquei JX4.

One new epimer pair of long-chain polyenes penicilqueis E (1) and F (2), and one new long-chain polyene pinophol G (3), along with one known compound (4), were obtained from EtOAc extract of the mangrove-derived fungus Penicillium herquei JX4. Their structures were elucidated by detailed analysis of comprehensive spectroscopic data. 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.

Cytotoxic Indole Diterpenoids from a Sphagneticola trilobata-Derived Fungus Aspergillus sp. PQJ-1.

Two new indole diterpene derivatives, 5S-hydroxy-ß-aflatrem (1) and 14R-hydroxy-ß-aflatrem (2), along with one known analogue, 14-(N,N-dimethl-L-valyloxy)paspalinine (3), were isolated from the fermentation broth of the fungus Aspergillus sp. PQJ-1 derived from Sphagneticola trilobata. The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. All the compounds (1-3) were evaluated for their cytotoxicity against A549, Hela, Hep G2, and MCF-7 cell lines. Compounds 1 and 2 exhibited selective inhibition against Hela cells. Further studies showed that 1 significantly induced apoptosis and suppressed migration and invasion in Hela cells. Moreover, 1 could up-regulate pro-apoptotic genes BAX and Caspase-3 and down-regulate anti-apoptotic genes Bcl-xL and XIXP.

Four Undescribed Pyranones from the Scutellaria formosana-Derived Endophytic Fungi Ascomycota sp. FAE17.

Four undescribed pyranone derivatives, named ascomycopyrones A-D (1-4), as well as one known analogue simplicilopyrone (5) (this is the first study to report the absolute configuration), were isolated from the endophytic fungus Ascomycota sp. FAE17 derived from the flowers of Scutellaria formosa. The structures of these pyranones were identified by comprehensive spectroscopic and MS analyses, and the absolute configurations were determined by their experimental and quantum chemical electronic circular dichroism (ECD) calculations. All isolated compounds were tested for various bioactivities, including antibacterial, cytotoxic activity, and NO inhibitory activity. Unfortunately, none of the compounds showed significant bioactivities.

Zeylleucapenoids A-D, Highly Oxygenated Diterpenoids with Anti-Inflammatory Activity from Leucas zeylanica (L.) R. Br.

Four previously undescribed highly oxygenated diterpenoids (1-4), zeylleucapenoids A-D, characterized by halimane and labdane skeletons, were isolated from the aerial parts of Leucas zeylanica. Their structures were elucidated primarily via NMR experiments. The absolute configuration of 1 was established using theoretical ECD calculations and X-ray crystallographic analysis, whereas those for 2-4 were assigned using theoretical ORD calculations. Zeylleucapenoids A-D were tested for anti-inflammatory activity against nitric oxide (NO) production in RAW264.7 macrophages, of which only 4 showed significant efficacy with an IC50 value of 38.45 µM. Further, active compound 4 was also evaluated for the inhibition of the release of pro-inflammatory cytokines TNF-α and IL-6 and was found to have a dose-dependent inhibitory effect, while it showed nontoxic activity for zebrafish embryos. A subsequent Western blotting experiment revealed that 4 inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, molecular docking analysis indicated that the possible mechanism of action for 4 may be bind to targets via hydrogen and hydrophobic bond interactions.

Biological Secondary Metabolites from the Lumnitzera littorea-Derived Fungus Penicillium oxalicum HLLG-13

Five new compounds, including two cyclopiane diterpenes conidiogenones J and K (1-2), a steroid andrastin H (5), an alkaloid (Z)-4-(5-acetoxy-N-hydroxy-3-methylpent-2-enamido) butanoate (6), and an aliphatic acid (Z)-5-acetoxy-3-methylpent-2-enoic acid (7), together with ten known compounds (3-4 and 8-15) were isolated from the EtOAc extract of the fermentation broth of the Lumnitzera littorea-derived fungus Penicillium oxalicum HLLG-13. Their structures were elucidated by 1D, 2D NMR, and HR-ESI-MS spectral analyses. The absolute configurations of 1, 2, 5, and 8 were determined by quantum chemical electronic circular dichroism (ECD) calculations, and the absolute configuration of 8 was determined for the first time. Compound 15 was a new natural product, and its NMR data were reported for the first time. Compounds 5 and 9-14 exhibited antibacterial activities against Staphylococcus epidermidis and Candida albicans, with MIC values ranging from 6.25 to 25 µg/ mL. Compounds 1-6 and 9-14 showed significant growth inhibition activities against newly hatched Helicoverpa armigera Hubner larvae, with IC50 values ranging from 50 to 200 µg/mL.

Talaromarins A-F: Six New Isocoumarins from Mangrove-Derived Fungus Talaromyces flavus TGGP35.

Six new isocoumarin derivative talaromarins A-F (1-6), along with 17 known analogues (7-23), were isolated from the mangrove-derived fungus Talaromyces flavus (Eurotiales: Trichocomaceae) TGGP35. Their structures were identified by detailed IR, UV, 1D/2D NMR and HR-ESI-MS spectra. The absolute configurations of new compounds were determined by the modified Mosher's method and a comparison of their CD spectra with dihydroisocoumarins described in the literature. The antioxidant, antibacterial, anti-phytopathogenic and inhibitory activity against α-glucosidase of all the isolated compounds were tested. Compounds 6-11, 17-19 and 21-22 showed similar or better antioxidant activity than the IC50 values ranging from 0.009 to 0.27 mM, compared with the positive control trolox (IC50 = 0.29 mM). Compounds 10, 18, 21 and 23 exhibited strong inhibitory activities against α-glucosidase with IC50 values ranging from 0.10 to 0.62 mM, while the positive control acarbose had an IC50 value of 0.5 mM. All compounds showed no antibacterial or anti-phytopathogenic activity at the concentrations of 50 µg/mL and 1 mg/mL, respectively. These results indicated that isocoumarins will be useful to developing antioxidants and as diabetes control agents.

Design, Semisynthesis, Insecticidal and Antibacterial Activities of a Series of Marine-Derived Geodin Derivatives and Their Preliminary Structure-Activity Relationships.

To enhance the biological activity of the natural product geodin (1), isolated from the marine-derived fungus Aspergillus sp., a series of new ether derivatives (2-37) was designed and semisynthesized using a high-yielding one-step reaction. In addition, the insecticidal and antibacterial activities of all geodin congeners were evaluated systematically. Most of these derivatives showed better insecticidal activities against Helicoverpa armigera Hübner than 1. In particular, 15 showed potent insecticidal activity with an IC50 value of 89 µM, comparable to the positive control azadirachtin (IC50 = 70 µM). Additionally, 5, 12, 13, 16, 30 and 33 showed strong antibacterial activity against Staphylococcus aureus and Aeromonas salmonicida with MIC values in the range of 1.15-4.93 µM. The preliminary structure-activity relationships indicated that the introduction of halogenated benzyl especially fluorobenzyl, into 1 and substitution of 4-OH could be key factors in increasing the insecticidal and antibacterial activities of geodin.

[Chemical constituents with α-glucosidase inhibitory activities from seeds of Morinda citrifolia (Noni)].

The present study investigated the chemical constituents and inhibitory activities against α-glucosidase from the seeds of Morinda citrifolia(Noni) by the chromatographic technique and semi-preparative HPLC.Fifteen compounds were isolated from the ethyl acetate extract of the seeds, and their structures were identified on the basis of physiochemical characteristics and spectroscopic data as(9S,2E,4Z,7Z)-9-hydroxydeca-2,4,7-trienoic acid(1), azelaic acid(2), scopoletin(3), ursolic acid(4), quercetin(5), cyclo-(L-Leu-L-Ile)(6), cyclo-(L-Phe-L-Ile)(7), cyclo-(L-Phe-L-Val)(8), cyclo-(L-Leu-L-Val)(9), cyclo-(L-Phe-L-Leu)(10), caffeic acid(11), 3,4-dihydroxycinnamaldehyde(12), p-hydroxybenzoic acid(13), p-hydroxy-cinnamic acid(14), and p-hydroxyphenethyl alcohol(15).Among them, compound 1 was a new fatty acid and compounds 7-10 and 12 were isolated from Morinda plant in the Rubiaceae family for the first time.Compounds 1, 2 and 4-15 were isolated from the seeds of M.citrifolia(Noni) for the first time.All isolated compounds were evaluated for the inhibitory activities against α-glucosidase and compounds 3-5 showed potential inhibitory activity with IC_(50) values of 160, 133, and 120 µmol·L~(-1), respectively.

Synthesis and anti-tumor activity of marine alkaloids.

Marine alkaloids were divided into five categories from the perspective of anti-tumor activity. The optimization process, chemical synthesis, anti-tumor activity evaluation and structure-activity relationship of various compounds were discussed.

Synthesis, activity and mechanism for double-ring conjugated enones.

The relationship between TLR4 and inflammation-related diseases has been paid more and more attention. The studies have shown that TLR4/NF-κB signaling pathway plays an important role in the transmission of inflammatory signals. A large number of pro-inflammatory factors, chemokines, adhesion factors, TLR4 and its ligands interact with each other, and jointly promote the development of diseases. In this work, 8 target compounds were synthesized to screen the inhibitory activity of TLR4 in vitro. The results of TLR4 inhibition test in vitro showed that the double-ring conjugated enones had a good inhibitory activity, and the IC50 value of compound 4f was 0.56 ± 0.10 µM, and it was superior to the positive control methotrexate. To further study the anti-inflammatory effect and mechanism of double-ring conjugated enones by using LPS induced rat synovial cell inflammation model. The results of the mechanism test showed that compound 4f could effectively promote the apoptosis of rat synovial cells, and the mechanism might be related to the up-regulation of the expression of apoptosis-related protein Caspase-3. In addition, compound 4f could significantly inhibit the increase of inflammatory factors TNF-α, IL-1ß and IL-6 in rat synovial cells induced by LPS, showing a good anti-inflammatory activity. In the TLR4/NF-κB signaling pathway test of rat synovial cells, compound 4f can effectively regulate the expression levels of TLR4, MyD88, NF-κB and IκB related proteins in TLR4/NF-κB signaling pathway, which may be due to its inhibition of LPS-induced inflammation in rat synovial cells. At the same time, it inhibits the abnormal proliferation of cells and its important mechanism promoted of apoptosis.

Preparations and antioxidant activities of sesamol and it's derivatives.

Antioxidants is a kind of substances that can effectively inhibit the oxidation reaction of free radicals. There are many chemical components with antioxidant activity in natural products. Sesamol is one of the natural products with antioxidant activity, and it is often used as an antioxidant in food, medicine and other fields. In the present study, sesame was used as the extraction raw material for the extraction and separated of sesamol with antioxidant activity. On this basis, a total 10 of sesamol derivatives were synthesized by two steps reaction with sesamol as starting material. The antioxidant activity of these sesamol derivatives were tested, and the test results showed that these sesamol derivatives had a good antioxidant activity, among them, compound 4d had the best antioxidant activity. Sesamol derivatives can be used as an antioxidant in food, medicine and other fields and it needs a further study.

Austins-Type Meroterpenoids from a Mangrove-Derived Penicillium sp.

Three unusual austins-type meroterpenoids penicianstinoids C-E (1-3) were obtained from the mangrove-derived fungus Penicillium sp. TGM112. The structures of 1-3 including absolute configurations were determined by detailed NMR, MS spectroscopic data, X-ray diffraction analysis, and calculated electronic circular dichroism data. Penicianstinoid C (1) was the first austins-type meroterpenoid with a unique 6/6/6/5 rearranged tetracyclic skeleton possessing two unusual spirocyclic moieties (2-oxaspiro[5.5]undeca-4,7-dien-3-one and 6-methylene-2-oxaspiro[4.5]decane-1,4-dione). Penicianstinoid D (2) was an unusual austins-type meroterpenoid with a 6/6/6/6 tetracyclic skeleton containing an octahydro-2H-chromen-2-one unit. Penicianstinoid E (3) possessed a 6/5/6/6/6/5 fused hexacyclic skeleton with an uncommon five-membered ether ring system. The plausible biosynthetic pathway of 1-3 is also proposed. Compounds 1 and 3 inhibited the growth of newly hatched Helicoverpa armigera Hubner larvae with IC50 values of 100 and 200 µg/mL, respectively.