Analgesics, Non-Narcotic ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Azetidines ; chemical synthesis ; chemistry ; pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Molecular Structure ; Nicotinic Agonists ; chemical synthesis ; chemistry ; pharmacology ; Pyridines ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship

To design and synthesize the hepatic targeting anticancer prodrug with norcantharidin (NCTD-Gal) conjugating structure, galactosylated NCTD derivatives were synthesized from NCTD analogues modified by a series of amino acids via acylation, hydrolysis, glycosylation and deacetylation. Seven new compounds were synthesized as beta-O-glycosides and characterized by IR, MS, NMR and element analysis. The compound 4a was chosen for the inchoate antitumor experiments on mice. The result showed that the antitumor inhibition rate of 4a groups with medium and high dose are clearly higher than that of NCTD group, which suggests that anticancer effect of NCTD is improved at a certain degree by galactosylation.
Animals ; Antineoplastic Agents ; chemical synthesis ; pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; chemical synthesis ; chemistry ; pharmacology ; Carcinoma, Hepatocellular ; pathology ; Cell Line, Tumor ; Drug Delivery Systems ; Female ; Galactose ; chemistry ; Humans ; Liver Neoplasms ; pathology ; Male ; Mice ; Neoplasm Transplantation ; Prodrugs ; chemical synthesis ; pharmacology

This research is to study the relationship between HPLC fingerprints of Moutan Cortex, Paeoniae Radix Rubra and Paeoniae Radix Alba and their activity on lipopolysaccharide-induced acute lung injury. HPLC fingerprints of each extract of Moutan Cortex,Paeoniae Radix Rubra and Paeoniae Radix Alba were established by an optimized HPLC-MS method. The activities of all samples against protein and tumor necrosis a factor were tested by the model of lipopolysaccharide-induced acute lung injury. The possible relationship between HPLC-MS fingerprints and the activitieswere deduced by the Partial least squares regression analysis method. Samples were analyzed by HPLC-MS/MS to identify the major peaks. The results showed that each sample had some effect on acute lung injury. Four components with a lager contribution rate of efficacy were calculated by the research of spectrum-effect relationship. Moutan Cortex exhibited good activity on acute lung injury, and gallic acid, paeoniflorin, galloylpaeoniflorin and paeonol were the main effective components.
Acetophenones ; chemistry ; pharmacology ; Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Bridged Bicyclo Compounds, Heterocyclic ; chemistry ; pharmacology ; Chromatography, High Pressure Liquid ; methods ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Gallic Acid ; chemistry ; pharmacology ; Glucosides ; chemistry ; pharmacology ; Lipopolysaccharides ; pharmacology ; Male ; Monoterpenes ; chemistry ; pharmacology ; Paeonia ; chemistry ; Plant Roots ; chemistry ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry ; methods

Norcantharidin (NCTD) is the demethylated form of cantharidin, which is the active substance of mylabris. To examine the pathway of NCTD-induced A375-S2 cell death, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-dipheyltetrazolium bromide (MTT) assay, photomicroscopical observation, DNA agarose gel electrophoresis, caspase activity assay and Western blot analysis were carried out. A375-S2 cells treated with NCTD exhibited several typical characteristics of apoptosis. The inhibitory effect of NCTD on human melanoma, A375-S2 cells, was partially reversed by the inhibitors of pan-caspase, caspase-3 and caspase-9. The activities of caspase-3 and -9 were significantly increased after treatment with NCTD at different time. The expression of inhibitor of caspase-activated DNase was decreased in a time-dependent manner, simultaneously, the ratio of Bcl-2/Bax or Bcl-xL/Bax was decreased and the expression ratio of proteins could be reversed by caspase-3 inhibitor. The expression of cytochrome c in cytosol was increased after NCTD treatment and caspase- 3 inhibitor had no significant effect on the up-regulation of cytochrom c. These results suggest that NCTD induced A375-S2 cell apoptosis and the activation of caspase and mitochondrial pathway were involved in the process of NCTD-induced A375-S2 cell apoptosis.
Animals ; Apoptosis/*physiology ; Bicyclo Compounds, Heterocyclic/chemistry/metabolism/*pharmacology ; Caspases/antagonists & inhibitors/*metabolism ; Cell Line, Tumor/*drug effects ; Cell Shape ; DNA Fragmentation ; Enzyme Activation ; Humans ; Mitochondria/*metabolism ; Molecular Structure ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Signal Transduction/*physiology

Tumor migration/invasion is the main cause of tumor progression and STAT3 is needed to enhance tumor migration/invasion by up-regulating MMP-9. Thus, agents that inhibit STAT3 activation may be used as an anticancer drug. We present herein that 6-methyl-2-propylimino-6, 7-dihydro-5H-benzo [1, 3]-oxathiol- 4-one (LYR71) , a derivative of trimeric resveratrol, has an anticancer activity through inhibition of STAT3 activation. We found that LYR71 suppressed STAT3 activation and inhibited the expression and activity of MMP-9 in RANTES-stimulated breast cancer cells. In addition, LYR71 reduced RANTES-induced MMP-9 transcripts by blocking STAT3 recruitment, dissociating p300 and deacetylating histone H3 and H4 on the MMP-9 promoter. Furthermore, LYR71 inhibited tumor migration/invasion in RANTES-treated breast cancer cells and consequently blocked tumor progression in tumor-bearing mice. Taken together, the results of this study suggest that LYR71 can be therapeutically useful due to the inhibition effect of STAT3-mediated MMP-9 expression in breast cancer cells.
Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology ; Blotting, Western ; Breast Neoplasms/genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Chromatin Immunoprecipitation ; Female ; Gene Expression/drug effects ; Humans ; Imines/chemistry/*pharmacology ; Immunohistochemistry ; Mammary Neoplasms, Experimental/pathology/prevention & control ; Matrix Metalloproteinase 9/genetics/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Structure ; Phosphorylation/drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; STAT3 Transcription Factor/genetics/*metabolism ; Stilbenes/chemistry ; Xenograft Model Antitumor Assays/methods

Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drosophila/enzymology/metabolism ; Drosophila Proteins/antagonists & inhibitors/metabolism ; Enzyme Activation/*drug effects ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Janus Kinase 3/*antagonists & inhibitors/metabolism ; Lymphoma/enzymology/*metabolism ; Phosphorylation/drug effects ; STAT Transcription Factors/antagonists & inhibitors/metabolism ; STAT3 Transcription Factor/*antagonists & inhibitors/metabolism ; Signal Transduction/*drug effects