Wen-Jie Wang

Synthesis and Structure–Activity Relationships of Quaternary Coptisine Derivatives as Potential Anti-ulcerative Colitis Agents

Thirty quaternary coptisine derivatives from a synthesized library were found to activate the in vitro transcription of x-box-binding protein 1 (XBP1). Among these, the dihydrocoptisines were demonstrated by in vitro XBP1 transcriptional activity assays and animal experiments to be much more active anti-ulcerative colitis (UC) agents than quaternary coptisines, tetrahydrocoptisines, and the positive control. Unsubstituted dihydrocoptisine exhibited more significant anti-UC efficacy than dihydrocoptisines substituted at the C-8 or C-13 position. The EC50 value of dihydrocoptisine for XBP1 transcriptional activation was 2.25 nM. Dihydrocoptisine exhibited a significant dose-effect relationship, as indicated by biomarkers in in vitro and in vivo experiments. According to this study, the starting materials reductive states and the substitution patterns of the dihydrocoptisines were determined to be the critical parameters for modulating their anti-UC efficacy, and the dihydrocoptisine skeleton was designated as the key pharmacophore. The synthesized dihydrocoptisine is a promising lead for developing anti-UC drugs.

Cembranoids from the Gum Resin of Boswellia carterii as Potential Antiulcerative Colitis Agents

Eight new cembranoids, boscartins A-H (1, 2, and 4-9), and the known incensole oxide were isolated from the gum resin of Boswellia carterii. The absolute configurations of 1, 2, 4, and incensole oxide were unequivocally resolved using single-crystal X-ray diffraction analysis with Cu Kα radiation, and the absolute configuration of 5 was resolved via electronic circular dichroism data. The antiulcerative colitis activities of the compounds were evaluated in an in vitro x-box-binding protein 1 (XBP 1) transcriptional activity assay using dual luciferase reporter detection. At 10 μM, compounds 1, 5, 6, and 7 significantly activated XBP 1 transcription with EC50 values of 0.34, 1.14, 0.88, and 0.42 μM, respectively, compared with the pGL3-basic vector control.

Osteoclast-inhibiting saikosaponin derivatives from Bupleurum Chinense

Five new saikosaponins, saikosaponin w (1), 21β-hydroxysaikosaponin b2 (2), 6″-O-acetylsaikosaponin e (3), 6″-O-acetylsaikosaponin b1 (4), and 6″-O-acetylsaikosaponin b3 (5), along with twenty-two known ones (6-27), have been isolated from the roots of Bupleurum chinense. Their structures were elucidated on the basis of detailed spectroscopic analysis, including mainly 1D and 2D NMR and HRESI-MS, qualitative chemical methods, and comparison with the literatures. Osteoclast-inhibiting activity of some of the isolated compounds was evaluated in vitro, with five ones have shown significant activity by inhibitory rates ranging from 48.3% to 56.1% at the concentration of 10μM and with significant differences among groups observed.

The protective effect of epicatechin on experimental ulcerative colitis in mice is mediated by increasing antioxidation and by the inhibition of NF-κB pathway

BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory intestinal disease. It is necessary to find out new effective drugs for UC. In our study epicatechin extracted from grape seed by our institute for the first time could treat UC effectively. Then anti-UC mechanisms of epicatechin were elucidated in vivo and in vitro. METHODS Dextran sulfate sodium (DSS)-induced acute UC mice model was used to evaluate the activity of epicatechin and its properties against UC. Then its anti-inflammatory and antioxidant effects were evaluated as follows: the concentrations of TNF-α and IL-6 in the colon supernatants were determined by ELISA. NO and MPO were assayed by Griess method and commercial kit respectively. NF-κB were determined by NF-κB-Dependent Reporter Gene Expression Assay and Western Blotting respectively. Antioxidant factors such as SOD, MDA, GSH-Px and CAT were also measured in colon tissues and cell supernatant stimulated by LPS respectively. RESULTS In C57BL/6J mice model with DSS-induced UC, epicatechin was able to decrease the disease activity index and colon macroscopic damage index scores, reduce body weight loss, and significantly relieve colon contracture and crypt damage. TNF-α, IL-6, NO, MPO and MDA were reduced in the mice administered epicatechin, whereas antioxidant enzymes showed increased activity in epicatechin-treated mice and cell line respectively. Furthermore, inhibition effect on NF-κB activation by epicatechin were demonstrated in vivo and in vitro. CONCLUSIONS Epicatechin has inhibitory effect on DSS-induced acute UC. This effect is mainly due to its antioxidant effect and the inhibition of inflammatory molecules related to NF-κB pathway.

New synthetic method of 8-oxocoptisine starting from natural quaternary coptisine as anti-ulcerative colitis agent.

Quaternary coptisine (1), a natural bioactive quaternary protoberberine alkaloid (QPA), was treated with potassium ferricyanide in aqueous solution of 5 N sodium hydroxide leading to the acquisition of 8-oxocoptisine (2) with much higher yield than reported in the literature. This is the first report of the oxidation of a natural QPA by applying potassium ferricyanide as an oxidant. 8-Oxocoptisine showed significant anti-ulcerative colitis efficacy in vitro with EC50 value being 8.12 × 10− 8 M.

Inhibitory effects of SY0916, a platelet-activating factor receptor antagonist, on the angiogenesis of human umbilical vascular endothelial cells

SY0916 is a novel platelet-activating factor receptor antagonist. The objective of this study is to explore the anti-angiogenesis effects of SY0916 on human umbilical vascular endothelial cell (HUVEC) and to understand its possible mechanism. The effect of SY0916 on proliferation of HUVEC was measured by the MTT method, whereas the effect of SY0916 on HUVEC chemotaxis was carried out by Boyden chamber assay. The activities of metalloproteinase (MMP)-9 and MMP-2 were detected using gelatin zymography, and the expression of intercellular adhesion molecules-1 (ICAM-1) was measured by Western blot analysis. The 2D tube formation experiment of HUVEC with 10% fetal calf serum on Matrigel was also evaluated. It was shown that SY0916 had significant inhibitory effects on the proliferation and the chemotaxis of HUVEC induced by phorbol-12-myristate-13-acetate in a positive dose-dependent manner. Furthermore, SY0916 could significantly suppress the activity of MMP-2 and MMP-9 and decrease the expression of ICAM-1 in HUVEC. In 2D tube formation test, SY0916 could effectively inhibit the formation of vascular structure on Matrigel. The results showed that SY0916 could block the chemotaxis of HUVEC, and then inhibit the tube formation on Matrigel. Such anti-angiogenesis effect of SY0916 on HUVEC might relate to downregulate the expressions of MMP-2, MMP-9, and ICAM-1.

Synthesis and Structure–Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1

In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose-effect relationships with EC50 values of 0.0708-0.0132 μM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs.

The antinociceptive effect and mechanism of action of SY0916.

Pain greatly affects the quality of life of people worldwide. Despite their demonstrated efficacy, currently used opioid drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with several adverse events. The identification of new therapeutic targets and the development of corresponding analgesics may represent novel approaches for effectively treating pain. SY0916 is a novel compound that was designed and synthesized by the Institute of Materia Medica, Chinese Academy of Medical Sciences. As demonstrated by the hot plate test, tail-flick test and the formalin test, SY0916 exerted strong peripheral and central antinociceptive effects. Western blot, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) results indicate that SY0916 induces its peripheral antinociceptive effect by suppressing the peripheral activity of inflammatory mediators such as prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-α) and 5-hydroxytryptamine (5-HT). Moreover, its central antinociceptive effect might be mediated by the down-regulation of PGE2 and TNF-α expression and the inhibition of p-p38 and NF-κB pathway signaling in glial cells. These findings demonstrate that SY0916 may serve as a promising analgesic candidate drug.

Three new lignan glucosides from the roots of Scutellaria baicalensis

Three new lignan glucosides, baicalensinosides A–C (1–3), were isolated from the roots of Scutellaria baicalensis. The structural elucidation was achieved by in-depth spectroscopic examinations and qualitative chemical test. Structurally, these compounds belong to the 3,4-dibenzyltetrahydrofuran-type lignan glycoside with a mono-hydroxyl substitution at the 7′-position of benzylidene group on the numbering system of lignans being one of their shared critical features. The anti-osteoporotic activity of the isolated compounds was assessed in an in vitro osteoprotegerin (OPG) transcriptional activity assay using dual luciferase reporter detection. At 10 μmol/L, compounds 1–3 increased the relative activating ratio of OPG transcription to 1.83, 0.84 and 0.98 times that of the control group, respectively.

Effects and mechanism of aromatic aminoketone SY0916 on osteoclastic bone destruction

AbstractAim:To study the effects and mechanism of aromatic aminoketone (SY0916) on bone destruction in vitro.Methods:MC3T3-E1 cells and bone marrow cells were co-cultured to obtain purified osteoclasts. The proliferation of osteoclast-like cells (OCLs) was determined by MTT assay. The number of osteoclasts was measured by tartrate-resistant acid phosphatase (TRAP) staining. The functioning of osteoclasts was determined by measuring the area of bone resorption pits on bone slices. MMP-9 secretion by osteoclasts was measured by an ELISA kit. Osteoclast apoptosis was detected by flow cytometry using an AnnexinV-FITC kit. Gene expression of RANK and MMP-9 in osteoclasts as well as RANKL and OPG in MC3T3-E1 cells was determined by real-time PCR.Results:SY0916 significantly inhibited the proliferation of OCLs, decreased both the total and average area of bone resorption pits, and dramatically inhibited the number of osteoclasts between concentrations of 0.01 and 10 μmol/L. Furthermore, SY0916 reversed IL-1β-mediated inhibition of osteoclast apoptosis and shortened osteoclast lifespan. In addition, SY0916 significantly inhibited the mRNA expression of RANK, RANKL, OPG, and MMP-9. However, the inhibition of OPG was weaker than that of RANKL. Accordingly, the ratio of RANKL to OPG mRNA expression in MC3T3-E1 cells was significantly decreased by SY0916. Meanwhile, the expression of MMP-9 protein in osteoclasts was inhibited by SY0916 between 0.01 and 10 μmol/L.Conclusion:SY0916 prevents osteoclastic bone destruction by inhibiting the proliferation and function of osteoclasts. The underlying mechanism for this effect involves the regulation of the RANKL-OPG-RANK axis, which determines the direction of bone metabolism.