Hai-Jing Zhang

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.

Interaction studies of an anticancer alkaloid, (+)-(13aS)-deoxytylophorinine, with calf thymus DNA and four repeated double-helical DNAs.

Background: Phenanthroindolizidine alkaloids are a family of plant-derived compounds with significant antineoplastic activity. The specific biomolecular targets of these alkaloids have not yet been clearly identified. (+)-(13aS)-deoxytylophorinine is a new phenanthroindolizidine alkaloid originally extracted from the roots of Tylophora atrofolliculata and Tylophora ovata in our institute. (+)-(13aS)-deoxytylophorinine exerts both in vitro and in vivoanticancer activities. Methods: The in vivo anticancer effects and toxicity of this compound were investigated in mice, and interactions between this compound and double-helical DNA sequences were studied in detail with circular dichroic spectroscopy and fluorescence spectroscopy. Viscosity measurements were applied to check the interactive mode between this compound and DNA. Results: Potent anticancer effects were observed in vivo. Also, concentration-dependent interactions were observed and this compound seemed to interact in a sequence-specific manner with AT-repeated sequences of double-helical DNA. Such interactions were proved to be intercalating by viscosity measurements. Conclusions: Anticancer alkaloid (+)-(13aS)-deoxytylophorinine can have sequence-specific interactions with DNA in an intercalating manner.

Anticancer effect and neurotoxicity of S-(+)-deoxytylophorinidine, a new phenanthroindolizidine alkaloid that interacts with nucleic acids.

Phenanthroindolizidine alkaloids are a family of plant-derived compounds with significant antineoplastic activity as well as other effects like antiamebicidal, antiviral, and anti-inflammatory activities. The specific biomolecular targets of these compounds have not yet been clearly identified. S-(+)-Deoxytylophorinidine (CAT) is a new phenanthroindolizidine alkaloid, originally extracted from the roots of Tylophora atrofolliculata and Tylophora ovata. Potent anticancer activity was observed in vitro and in vivo. Neurotoxicity of CAT was also studied and it was far less serious than that of vinblastine. Interactions between this compound and DNA had been studied in detail in our laboratory previously, and we further studied its interactions with RNA.

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.

Activity of the potent dual Abl/Src tyrosine kinase inhibitor FB2 against Bcr–Abl positive cell lines in vitro and in vivo

We have previously shown the inhibition of the small-molecule inhibitor FB2 on imatinib-sensitive and resistance CML cell lines with the wild-type Bcr-Abl fusion gene. Here we report the potent and selective antiproliferation on FB2 on transfected Ba/F3 p210 cell lines expressing various isoforms of Bcr-Abl (wild-type, Y253F, T315I). FB2 which orients Bcr-Abl and Src kinase activities, is shown to override imatinib-resistance CML involving Y253F mutation in the Abl kinase domain of the fusion protein except T315I in vivo and in vitro. Thus, we present FB2 that displays potency toward Bcr-Abl and Src as the molecular target, and which could potentially be used to override drug resistance in CML.

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.