Norwogonin aids in fighting MRSA-induced pneumonia by targeting agrAC to inhibit α-hemolysin production.

The increasing prevalence of infections related to methicillin-resistant Staphylococcus aureus (MRSA) necessitates the exploration of innovative therapeutic strategies that diverge from conventional antibiotic treatments. This is imperative to effectively combat resistance and manage these infections. The adoption of antivirulence strategies has emerged as a particularly promising avenue. This approach applies a heightened selective pressure on pathogens, thereby diminishing the likelihood of bacteria evolving resistance to antibiotics. In our pursuit of novel therapeutics for treating MRSA infections, we have focused on agents that inhibit the virulence of S. aureus without impeding its growth, aiming to minimize the development of drug resistance. α-Hemolysin, a critical virulence factor encoded by the hla gene, is a cytotoxin that forms pores in host cell membranes and plays a pivotal role in the progression of disease during bacterial infections. Herein, we identified that norwogonin could effectively inhibit Hla production via targeting agrAC, a crucial protein in quorum sensing, resulting in dose-dependent inhibition of hemolytic activity without suppressing S. aureus growth. In vitro assays illustrated that norwogonin decreased the thermal stability of agrAC, providing evidence of interaction between norwogonin and agrAC. Meanwhile, norwogonin alleviated Hla-mediated A549 cell damage and reduced lactate dehydrogenase release. In vivo studies suggested that norwogonin treatment blocked the establishment of a mouse model of pneumonia caused by S. aureus USA300. Notably, norwogonin enhanced the antibacterial potency of oxacillin. In conclusion, norwogonin is a promising candidate for treating S. aureus infections, offering a novel alternative to traditional antibiotics by targeting virulence factors and enhancing the efficacy of existing treatments.

The evaluation of hepatoprotective effects of flavonoids from Scorzonera austriaca Wild against CCl4-induced acute liver injury in vitro and in vivo.

Scorzonera austriaca Wild is a traditional herbal medicine; however, little is known with regard to the effect of flavonoids from S. austriaca (FSA) on liver injury induced by Carbon tetrachloride (CCl4), especially the mechanism remains unknown. Therefore, our paper was designed to investigate the hepatoprotective effect of FSA against CCl4-induced acute liver injury in vitro and in vivo, with focus on its potential mechanism. The purity of FSA prepared by using polyporous resin column chromatography could reach 94.5%, and seven flavonoid compounds in FSA were identified by using LC-ESI-MS analysis. In vivo results showed that FSA markedly decreased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and malonaldehyde (MDA) and increased the contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Furthermore, in vivo and in vitro results confirmed that FSA could inhibit inflammatory response, as evidenced by decreasing the levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) through inactivating toll-like receptor-4/nuclear factor-κB (TLR4/NF-κB) signaling pathway. FSA activated autophagy by increasing the ratio of LC3B-II/I and decreasing the protein level of p62 so as to exert its hepatoprotective effect. In general, these evidences suggested that FSA is likely to serve as a potential material for the drugs against chemical hepatic injury.

Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors.

Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ineffective. Therefore, the protein encoded by mcr-1, MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound 3 as a potential MCR-1 inhibitor by virtual screening, and 26 compound 3 derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound 6g, 6h, 6i, 6n, 6p, 6q, and 6r displayed more potent activity than compound 3. Notably, 25 µΜ of compound 6p or 6q combined with 2 µg·mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing mcr-1, which exhibited the most potent activity. In the enzymatic assay, we elucidate that 6p and 6q could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that 6p and 6q could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors.

Development of an LC-MS/MS method for quantification of two pairs of isomeric flavonoid glycosides and other ones in rat plasma: Application to pharmacokinetic studies.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous determination of six flavonoid glycosides - isoorientin (1), orientin (2), 2″-O-ß-d-xylopyranosyl isoorientin (3), 2″-O-ß-d-xylopyranosyl isovitexin (4), 6-C-l-α-arabipyranosyl vitexin (5) and vitexin (6) - in rat plasma using isoquercitrin as the internal standard (IS). Plasma samples were prepared by a one-step protein precipitation with acetonitrile. Chromatographic analysis was carried out on a 25 cm C18 column with a gradient mobile phase consisting of acetonitrile and 0.1% aqueous formic acid. Six analytes and IS were detected through electrospray ionization in negative-ion selection reaction monitoring mode. The mass transitions were as follows: m/z 447.2 → 327.0 for 1, m/z 447.2 → 327.0 for 2, m/z 579.3 → 458.9 for 3, m/z 563.0 → 293.1 for 4, m/z 563.0 → 353.0 for 5, m/z 431.1 → 311.1 for 6, and m/z 463.1 → 300.2 for IS. Calibration curves exhibited good linearity (r2 > 0.9908) over a wide concentration range for all compounds. Intra- and inter-day precision (RSD, %) at four different levels were both <14.2% and the accuracy (RE, %) ranged from -11.9 to 12.0%. The extraction recoveries of the six components ranged from 88.2 to 103.6%. The validated assay was successfully applied to the pharmacokinetic studies of the six components in male rat plasma after intravenous administration of total flavonoids of Scorzonera austriaca Wild.

New Triterpenoid Saponins from the Herb Hylomecon japonica.

Background: Hylomecon japonica, a plant of the Papaveraceae family which is well-known for the alkaloids they produce, is a perennial plant widely distributed in the northeast, central and east regions of China. Although a variety of chemical constituents, including alkaloids, flavonoids, and megastigmoids, have been isolated from H. japonica, the investigation of saponins in H. japonica has not been reported until now. Methods: Various separation techniques, including polyporous resin column chromatography, silica gel column chromatography and hemi-preparative HPLC were applied to the isolation of triterpenoid saponins, and chemical methods such as acid hydrolysis and spectroscopic methods including HRESIMS and NMR were applied to their structure elucidation, and the XTT reduction method was used to assay cytotoxicity. Results: Two new triterpenoid saponins, named hylomeconoside A (1) and B (2) which were identified as 3-O-ß-d-galactopyranosyl-(1→2)-ß-d-glucuronopyranosyl-gypsogenin-28-O-ß-d-xylopyranosyl-(1→3)-ß-d-xylopyranosyl-(1→4)-α-l-rhamnopyranosyl-(1→2)-ß-d-quinovopyranoside (1) and 3-O-ß-d-galactopyranosyl-(1→2)-ß-d-glucuronopyranosyl-gypsogenin-28-O-ß-d-xylopyranosyl-(1→3)-ß-d-xylopyranosyl-(1→4)-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside (2), and two known triterpenoid saponins identified as dubioside C (3) and lucyoside P (4) on the basis of spectroscopic and chemical evidence, were isolated from H. japonica. Compound 1 exhibited moderate cytotoxicity on MGC-803 and HL-60 cells, with IC50 values of 43.8 and 32.4 µg·mL-1, respectively. Conclusions: Compounds 1 and 2 are new saponins, and 1 is considered to be one of the antitumor principles in this plant. This is the first time that triterpenoid saponins have been isolated from plants of the Papaveraceae family.

Preparative Separation and Purification of the Total Flavonoids in Scorzonera austriaca with Macroporous Resins.

The use of macroporous resins for the separation and purification of total flavonoids to obtain high-purity total flavonoids from Scorzonera austriaca was studied. The optimal conditions for separation and purification of total flavonoids in S. austriaca with macroporous resins were as follows: D4020 resin columns were loaded with crude flavonoid extract solution, and after reaching adsorptive saturation, the columns were eluted successively with 5 bed volumes (BV) of water, 5 BV of 5% (v/v) aqueous ethanol and 5 BV of 30% (v/v) aqueous ethanol at an elute flow rate of 2 BV·h(-1). Total flavonoids were obtained from the 30% aqueous ethanol eluate by vacuum distillation recovery. The content of flavonoid compounds in the total flavonoids was 93.5%, which represents an improvement by about 150%. In addition, five flavonoid compounds in the product were identified as 2″-O-ß-d-xylopyranosyl isoorientin, 6-C-α-l-arabipyranosyl orientin, orientin, isoorientin and vitexin by LC-ESI-MS analysis and internal standard methods. The results in this study could represent a method for the large-scale production of total flavonoids from S. austriaca.

Flavonoid Glycosides and Their Derivatives from the Herbs of Scorzonera austriaca Wild.

Five flavonoid glycosides and two derivatives were isolated from the herbs of Scorzonera austriaca Wild by silica gel column chromatography and preparative HPLC. Their structures were identified, using chemical and spectroscopic methods, as 5,7,4'-trihydroxyflavone 6-C-(2''-O-ß-d-glucopyranosyl ß-d-glucopyranoside) (1), 5,7,3',4'-tetrahydroxyflavone 6-C-(2''-O-ß-d-glucopyranosyl ß-d-glucopyranoside) (2), quercetin 3-O-rutinoside (3), 5,7,4'-trihydroxyflavone 6-C-ß-d-glucopyranoside (4), 3'-methoxy-5,7,4'-trihydroxyflavone 6-C-ß-d-glucopyranoside (5), 5,7,4'-trihydroxyflavone 8-C-(6''-O-trans-caffeoyl ß-d-glucopyranoside) (6), and 5,7,3',4'-tetrahydroxyflavone 8-C-(6''-O-trans-caffeoyl ß-d-glucopyranoside) (7). Compounds 6 and 7 are new flavonoid glycoside derivatives, and compounds 1-5 were isolated from the herbs of Scorzonera austriaca for the first time. Compounds 6 and 7 were also assayed for their hepatoprotective activities with rat hepatocytes in vitro.

Pheonolic Compounds from the Fruits of Viburnum sargentii Koehne.

Seven phenolic compounds were isolated from the fruits of Viburnum sargentii Koehne by silica gel column chromatography and preparative HPLC. On the grounds of chemical and spectroscopic methods, their structures were identified as (-)-Epicatechin (1), 5,7,4'-trihydroxy-flavonoid-8-C-ß-D-glucopyranoside (2), 1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-α-L-rhamnopyranoxypropyl)-2-methoxyphenoxy]-1,3-propane-diol (erythro) (3), 1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-α-L-rhamnopyranoxypropyl)-2-methoxyphenoxy]-1,3-propanediol (threo) (4), (R)-4-hydroxylphenol O-(6-O-oleuropeoyl)-ß-D-glucopyranoside (5), (R)-3-methoxy-4-hydroxylphenol O-(6-O-oleuropeoyl)-ß-D-glucopyranoside (6), quercetin-3-O-rutinoside (7). Compounds 5 and 6 are new monoterpene phenolic glycosides, compounds 1, 3 and 4 were isolated from the Viburnum genus for the first time, and compounds 2 and 7 from the Viburnum sargentii Koehne for the first time. Compounds 1-7 were also assayed for their antioxidant activities with DPPH free radicals.

Isolation and identification of the phenolic compounds from the roots of Sanguisorba officinalis L. and their antioxidant activities.

Four phenolic compounds were isolated from the roots of Sanguisorba officinalis L. by silica gel column chromatography and preparative HPLC. On the basis of chemical and spectroscopic methods, their structures were identified as methyl 4-O-ß-D-glucopyranosy-5-hydroxy-3-methoxylbenzoate (1), 3,3',4'-tri-O-methylellagic acid (2), fisetinidol-(4α-8)-catechin (3), and (+)-catechin (4). Compound 1 is a new phenolic glycoside and compounds 2 and 3 were isolated from the Sanguisorba genus for the first time. Compounds 1­4 were also assayed for their antioxidant activities using the DPPH free radical assay.

Terpene glycosides from the roots of Sanguisorba officinalis L. and their hemostatic activities.

Guided by a hemostasis bioassay, seven terpene glycosides were isolated from the roots of Sanguisorba officinalis L. by silica gel column chromatography and preparative HPLC. On the grounds of chemical and spectroscopic methods, their structures were identified as citronellol-1-O-α-L-arabinofuranosyl-(1→6)-ß-D-glucopyranoside (1), geraniol-1-O-α-L-arabinofuranosyl-(1→6)-ß-D-glucopyranoside (2), geraniol-1-O-α-Larabinopyranosyl-(1→6)-ß-D-glucopyranoside (3), 3ß-[(α-L-arabinopyranosyl)oxy]-19α-hydroxyolean-12-en-28-oic acid 28-ß-D-glucopyranoside (4), 3ß-[(α-L-arabinopyranosyl)-oxy]-19α-hydroxyurs-12-en-28-oic acid 28-ß-D-glucopyranoside (ziyu-glycoside I, 5), 3ß,19α-hydroxyolean-12-en-28-oic acid 28-ß-D-glucopyranoside (6) and 3ß,19α-dihydroxyurs-12-en-28-oic acid 28-ß-D-glucopyranoside (7). Compound 1 is a new mono-terpene glycoside and compounds 2, 3 and 5 were isolated from the Sanguisorba genus for the first time. Compounds 1­7 were assayed for their hemostatic activities with a Goat Anti-Human α2-plasmin inhibitor ELISA kit, and ziyu-glycoside I (5) showed the strongest hemostatic activity among the seven terpene glycosides. This is the first report that ziyu-glycoside Ι has strong hemostatic activity.

Phenylpropanoids from Brachybotrys paridiformis Maxim. ex Oliv. and their anti-HBV activities.

Using chemical and spectroscopic data, this study on Brachybotrys paridiformis Maxim. ex Oliv. identified four undescribed phenylpropanoids, brachin A-C and brachoside A, together with nine other known compounds. The isolated compounds were tested for anti-hepatitis B virus activities in the HepG2.2.15 cell line. Among them, caffeic anhydride showed the most potent activity.

Phenylpropanoids from Brachybotrys paridiformis maxim. Ex oliv. And their anti-HBV activities (II).

Five undescribed phenylpropanoids, one undescribed phenolic glucoside, and sixteen known compounds were isolated from Brachybotrys paridiformis Maxim. Ex Oliv. The undescribed compounds were named brachoside B-C, brach acid A-B, brachnan A, and brachin D, respectively. Additionally, the anti-hepatitis B virus activities of all isolated compounds were studied. Among them, brachnan A, brach acid A, globoidnan A, 3-carboxy-6,7-dihydroxy-1-(3',4'-dihydroxy-phenyl)-naphthalene, and 3,4-dihydroxybenzaldehyde showed significant anti-hepatitis B virus activities.

Reactive oxygen species-responsive silk sericin microcapsules used for antioxidative stress damage.

Silk sericin microcapsules loaded with horseradish peroxidase (HRP) are prepared through protein self-assembly in a green environment containing enzymes to protect liver cells from alcohol damage. Load content and release dynamics of HRP in sericin microcapsules are investigated. The role of HRP-loaded microcapsules in hydrogen peroxide (H2 O2 ) degradation is demonstrated using electrochemical method. Furthermore, the effect of the HRP-loaded microcapsules on cells and intracellular reactive oxygen species (ROS) level is evaluated using an alcohol damage model in vitro. Results show that HRP can be loaded effectively in the sericin microcapsules and can be released ROS-responsively from microcapsules. Cell survival rate increases after suffering from alcohol damage due to the presence of HRP-loaded microcapsule, and the active oxygen content in cells is maintained at a stable level even when it remained in an environment with high alcohol concentration. We believe that the internalized sericin microcapsules maintain HRP activity intracellularly, allow controlled HRP release within a host cell, and show excellent ability in antioxidative stress injury.

Bioactive oleanane-type saponins from Hylomecon Japonica.

Six undescribed oleanane-type saponins, named as Hylomeconosides L-Q, were isolated from the whole herb of Hylomecon Japonica, their structures were determined by analysis of 1D and 2D-NMR (1H-1H COSY, HSQC, and HMBC) spectroscopic data, mass spectrometry (HRESI-MS) and chromatographic data (GC and LC). Their structures were identified as 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-ß-D-glucuronopyranosyl gypsogenin 28-O-ß-D-galactopyranosyl-(1 â†’ 3)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-L-arabinopyranoside; 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-ß-D-glucuronopyranosyl gypsogenin 28-O-ß-D-xylopyranosyl-(1 â†’ 4)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-quinovopyranoside; 3-O-ß-D-glucuronopyranosyl gypsogenin 28-O-ß-D-xylopyranosyl-(1 â†’ 3)-ß-D-xylopyranosyl-(1 â†’ 4)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-quinovopyranoside; 3-O-ß-D-xylopyranosyl-(1 â†’ 3)-ß-D-glucuronopyranosyl gypsogenin 28-O-ß-D-xylopyranosyl-(1 â†’ 4)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-quinovopyranoside; 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-[α-L-rhamnopyranosyl-(1 â†’ 3)]-ß-D-glucuronopyranosyl quillaic acid 28-O-ß-D-xylopyranosyl-(1 â†’ 3)-ß-D-xylopyranosyl-(1 â†’ 4)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-quinovopyranoside; 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-[α-L-rhamnopyranosyl-(1 â†’ 3)]-ß-D-glucuronopyranosyl quillaic acid 28-O-ß-D-xylopyranosyl-(1 â†’ 3)-ß-D-xylopyranosyl-(1 â†’ 4)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-galactopyranoside. Hylomeconosides L-Q showed selective cytotoxicities against human cancer cell lines A549, AGS, HeLa, Huh 7, HT29 and K562. These results represent a contribution to the chemotaxonomy of the saponins of Hylomecon Japonica and their bioactivities.

Studies on isolation and structural identification of saponins from the herb Hylomecon japonica and their bioactivities.

Three undescribed oleanane type triterpenoid saponins (1-3), along with one known saponin (4) were isolated from the whole herb of Hylomecon japonica. Their structures were elucidated by analysis of 1D and 2D-NMR (1H-1H COSY, HSQC, and HMBC) spectroscopic data, mass spectrometry (HR-ESI-MS) and chromatographic date (GC and LC) as 3-O-ß-d-glucopyranosyl-(1 â†’ 2)-ß-d-glucuronopyranosyl gypsogenin 28-O-ß-d-galactopyranosyl-(1 â†’ 3)-[ß-d-xylopyranosyl-(1 â†’ 4)]-α-l-rhamnopyranosyl-(1 â†’ 2)-ß-l-arabinopyranosyl ester (1), 3-O-ß-d-galactopyranosyl-(1 â†’ 2)-ß-d-glucuronopyranosyl gypsogenin 28-O-α-l-arabinopyranosyl-(1 â†’ 3)-[ß-d-xylopyranosyl-(1 â†’ 4)]-α-l-rhamnopyranosyl-(1 â†’ 2)-ß-l-arabinopyranosyl ester (2), 3-O-ß-d-galactopyranosyl-(1 â†’ 2)-ß-d-glucuronopyranosyl gypsogenin 28-O-ß-d-galactopyranosyl-(1 â†’ 3)-[ß-d-xylopyranosyl-(1 â†’ 4)]-α-l-rhamnopyranosyl-(1 â†’ 2)-ß-d-galactopyranosyl ester (3), 3-O-ß-d-galactopyranosyl-(1 â†’ 2)-[α-l-arabinopyranosyl-(1 â†’ 3)]-ß-d-glucuronopyranosyl gypsogenin 28-O-ß-d-glucopyranosyl-(1 â†’ 3)-[ß-d-xylopyranosyl-(1 â†’ 4)]-α-l-rhamnopyranosyl-(1 â†’ 2)-ß-d-fucopyranosyl ester (4). All saponins possess a partial sequence ß-d-galactopyranosyl-(1 â†’ 2)-ß-d-glucuronopyranosyl at C-3 of the aglycon. Compound 1 has cytotoxic activity against human colon cancer cell lines HT29, 3 against human gastric cancer cell lines AGS, and 4 against human lung cancer cell lines A549, AGS and HT29. Among them, compounds 3 and 4 showed significant inhibitory effect against AGS with IC50 value of 6.01 ± 1.4 µM, 3.66 ± 1.8 µM, respectively. These results represent a contribution to the chemotaxonomy of the saponins of Hylomecon japonica and their bioactivities.

Triterpenoid saponins from the herb Hylomecon japonica.

Six undescribed triterpenoid saponins, named as hylomeconoside C-H, were isolated from the EtOH extract of Hylomecon japonica. On the basis of spectroscopic and chemical evidence, their structures were identified as 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-ß-D-glucuronopyranosyl gypsogenin 28-O-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-L-arabinopyranoside; 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-ß-D-glucuronopyranosyl gypsogenin 28-O-ß-D-xylopyranosyl-(1 â†’ 4)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-L-arabinopyranoside; 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-[α-L-arabinopyranosyl-(1 â†’ 3)]-ß-D-glucuronopyranosyl gypsogenin 28-O-ß-D-glucopyranosyl-(1 â†’ 3)-[ß-D-xylopyranosyl-(1 â†’ 4)]-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-L-arabinopyranoside; 3-O-ß-D-galactopyranosyl-(1 â†’ 2)-ß-D-glucuronopyranosyl gypsogenin 28-O-ß-D-galactopyranosyl-(1 â†’ 3)-[ß-D-xylopyranosyl-(1 â†’ 4)]-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-fucopyranoside; 3-O-α-L-rhamnopyranosyl-(1 â†’ 3)-[ß-D-galactopyranosyl-(1 â†’ 4)]-ß-D-glucuronopyranosyl quillaic acid 28-O-ß-D-galactopyranosyl-(1 â†’ 3)-[ß-D-xylopyranosyl-(1 â†’ 4)]-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-fucopyranoside; 3-O-α-L-rhamnopyranosyl-(1 â†’ 3)-[ß-D-galactopyranosyl-(1 â†’ 4)]-ß-D-glucuronopyranosyl quillaic acid 28-O-ß-D-xylopyranosyl-(1 â†’ 3)-ß-D-xylopyranosyl-(1 â†’ 4)-α-L-rhamnopyranosyl-(1 â†’ 2)-ß-D-quinovopyranoside. The 50% EtOH extract showed moderate inhibitory activity on the human cancer cell line HeLa, HepG-2, MCF-7, A549, K562 and TE-1. And these six compounds were tested for cytotoxicity against K562. Among them, hylomeconoside H was found to be the most active on the K562 cell lines (IC50 6.60 µM).

Design, synthesis, and in-vivo evaluation of 4,5-diaryloxazole as novel nonsteroidal anti-inflammatory drug.

A series of 4,5-diaryloxazole analogs were designed and the interaction between oxaprozin and cyclooxygenase-2 studied by the docking method to improve the biological activity and reduce the gastrointestinal side effects of oxaprozin. Finally, 3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)-oxazole-2-yl) propanoic acid (NC-2142), the best candidate, was selected for synthesis and bioassay based on the screening result. NC-2142 could lower the tumefaction rates of back metatarsus in rats, as well as reduce the writhing times in mice. NC-2142 produced fewer gastric lesions than oxaprozin. After the aminosulfonyl group was introduced into the benzene ring of oxaprozin, its analgesic and anti-inflammatory activities remained unchanged, and it reduced the number of gastric lesions. This provided a feasible method for further structure modification and optimization of oxaprozin.

[Progress in the studies on small molecule IGF-1R inhibitors].

The importance of insulin-like growth factor 1 receptor (IGF-1R) signaling in malignant behaviour of tumour cells is well established. Inhibiting the activity of IGF-1R may result in striking apoptosis in malignant cells growing. IGF-1R antibodies which are currently in phase I and II clinical trials and several IGF-IR TKIs have preclinically been characterized. This review describes recent developments of small molecule tyrosine kinase inhibitors.

Structures of four new triterpenoid saponins from the leaves of Oplopanax elatus Nakai.

AIM: Isolation and structural elucidation of the triterpenoid saponins of Oplopanax elatus Nakai. METHODS: Solvent extraction and column chromatography were used to isolate the triterpenoid saponins, physico-chemical constants and spectroscopic analysis were employed for structural elucidation. RESULTS: Four newtriterpenoid saponins named cirenshenoside S (1), cirenshenoside T (2), cirenshenoside U (3) and cirenshenoside V (4) were isolated, and their structures were elucidated to be 3-O-beta-D-glucopyranosyl 3beta,23-dihydroxylup-20 (29)-en-28-oic acid 28-O-alpha-L-rhamnopyranosyl (1 --> 4)-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (1), 3-O-beta-D-glucopyranosyl hederagenin 28-O-alpha-L-rhamnopyranosyl (1 --> 4)-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (2), 3-O-beta-D-glucopyranosyl 3beta-hydroxyolean-9(11),12-dien-28-oic acid 28-O-alpha-L-rhamnopyranosyl (1 --> 4)-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (3) and 3alpha-hydroxyolean-12-dien-23,28-dioic acid 28-O-alpha-L-rhamnopyranosyl (1 --> 4 )-beta-D-glucopyranosyl (1 --> 6)-beta-D-glucopyranoside (4), respectively. CONCLUSION: Compounds 1-4 are new triterpenoid saponins and isolated from the leaves of Oplopanax elatus Nakai for the first time.

A caryophyllane-type sesquiterpene, caryophyllenol A from Valeriana amurensis.

A new caryophyllane derivative, caryophyllenol A, and a new germacrane derivative, isovolvalerenal D, together with 11 known sesquiterpenoids, were isolated from a petroleum ether partition of the roots and rhizomes of Valeriana amurensis. Structure elucidation of caryophyllenol A and isovolvalerenal D was accomplished on the basis of various spectroscopic techniques including HRESIMS and 2D NMR analyses. The structure of caryophyllenol A was further confirmed by X-ray crystallography and using quantum-chemical ECD calculation adopting TDDFT method. Caryophyllenol A and other eight sesquiterpenoids were evaluated for sedative activity with the model of Drosophila melanogaster, and eight of them showed the effect of prolonging the total sleeping time (TST) of D. melanogaster, displaying significant sedative action.