Characterization of the cytotoxicity of selected Chelidonium alkaloids in rat hepatocytes.

Phytomedicinal preparations containing extracts of the plant Chelidonium majus (Greater Celandine) have been used in the therapy of upper abdominal disorders. C. majus alkaloids (CAL) were suspected to be responsible for reported cases of liver symptoms including cases of acute liver failure in patients upon treatment with certain C.

Methylisoindigo and Its Bromo-Derivatives Are Selective Tyrosine Kinase Inhibitors, Repressing Cellular Stat3 Activity, and Target CD133+ Cancer Stem Cells in PDAC.

Indirubin is an active component of the herbal ingredient 'Danggui Longhui wan', which was used for the treatment of inflammation and chronic myeloid leukemia in China. The recent study showed its derivative methylisoindigo (also known as meisoindigo) preferentially targeting cancer stem cells (CSCs) in interference with AMPK and LKB1, the cellular metabolic sensors. In this study, we screened the effect of meisoindigo on a panel of 300 protein kinases and found that it selectively inhibited Stat3-associated tyrosine kinases and further confirmed its activity in cell based assays.

Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule.

Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in the search of water-soluble indirubins by introducing basic centers.

The Role of Indirubins in Inflammation and Associated Tumorigenesis.

Indirubin is the major active component of an herbal recipe 'Dangui Luhui Wan' () in traditional Chinese medicine (TCM). It is widely used in China for the treatment of inflammation, cancer, and other chronic diseases and is known for good efficiency and very low side effects. Primary studies on the mechanism of action revealed that indirubin and derivatives are potent ATP-competitive inhibitors of CDKs and GSK3ß achieving IC values down to the low nanomolar range.

Crystal structure of glycidamide: the mutagenic and genotoxic metabolite of acryl-amide.

The title compound, glycidamide (systematic name: oxirane-2-carboxamide), C3H5NO2, is the mutagenic and genotoxic metabolite of acryl-amide, a food contaminant and industrial chemical that has been classified as being probably carcinogenic to humans. Synthesized via the reaction of acrylo-nitrile and hydrogen peroxide, it crystallizes with both enanti-omers occurring as two crystallographically independent mol-ecules (A and B) in the asymmetric unit. They have similar conformations with an r.

Interim relative potency factors for the toxicological risk assessment of pyrrolizidine alkaloids in food and herbal medicines.

Pyrrolizidine alkaloids (PAs) are among the most potent natural toxins occurring in a broad spectrum of plant species from various families. Recently, findings of considerable contamination of teas/herbal infusions prepared from non-PA plants have been reported. These are obviously due to cross-contamination with minor amounts of PA plants and can affect both food and herbal medicines.

Methylisoindigo preferentially kills cancer stem cells by interfering cell metabolism via inhibition of LKB1 and activation of AMPK in PDACs.

Pancreatic ductal adenocarcinoma (PDAC) clinically has a very poor prognosis. No small molecule is available to reliably achieve cures. Meisoindigo is chemically related to the natural product indirubin and showed substantial efficiency in clinical chemotherapy for CML in China.

7,7'-Diazaindirubin--a small molecule inhibitor of casein kinase 2 in vitro and in cells.

Aza- and diaza-bisindoles were synthesized by coupling of 7-azaisatin, 7-azaoxindol, 7-azaindoxyl acetate, and their non-aza counterparts, respectively. Whereas 7,7'-diazaindigo (10) and 7,7'-diazaisoindigo (11) did not show antiproliferative activity in several human tumor cell lines up to 100 μM, 7-azaindirubin (12) and 7'-azaindirubin (13) were more active than the parent molecule, indirubin, in LXFL529L cells (human large cell lung tumor xenograft), and 7,7'-diazaindirubin (14) was exhibiting substantially enhanced growth inhibitory activity in these cells. In the NCI 60 cell line panel, 14 displayed antiproliferative activity preferentially in certain melanoma and non-small cell lung cancer cells.

Determination of the alkylpyrazine composition of coffee using stable isotope dilution-gas chromatography-mass spectrometry (SIDA-GC-MS).

A stable isotope dilution analysis based on gas chromatography-mass spectrometry analysis (SIDA-GC-MS) was developed for the quantitative analysis of 12 alkylpyrazines found in commercially available coffee samples. These compounds contribute to coffee flavor. The accuracy of this method was tested by analyzing model mixtures of alkylpyrazines.

Synthesis, topoisomerase-targeting activity and growth inhibition of lycobetaine analogs.

The plant alkaloid lycobetaine has potent topoisomerase-targeting properties and shows anticancer activity. Based on these findings, several lycobetaine analogs were synthesized mainly differing in their substituents at 2, 8 and 9 position and their biological activities were evaluated. The topoisomerase-targeting properties and cytotoxicity of these structural analogs were assessed in the human gastric carcinoma cell line GXF251L.

Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells.

Constitutively-activated JAK/Stat3 or Src/Stat3 signaling plays a crucial role in tumor cell survival, proliferation, angiogenesis and immune suppression. Activated JAK/Stat3 or Src/Stat3 has been validated as a promising molecular target for cancer therapy. However, prolonged inhibition of Src family kinases (SFKs) leads to reactivation of signal transducer and activator of transcript 3 (Stat3) and tumor cell survival through altered JAK/Stat3 interaction.

Indirubin derivatives modulate TGFβ/BMP signaling at different levels and trigger ubiquitin-mediated depletion of nonactivated R-Smads.

Regulatory Smads (R-Smads), Smad1/5/8 and Smad2/3, are the central mediators of TGFβ and BMP signaling pathways. Here, we screened indirubin derivatives, known kinase inhibitors, and observed strong interference with BMP signaling. We found that indirubin derivative E738 inhibited both TGFβ and BMP pathways through ubiquitin-proteasome-mediated depletion of total R-Smad pools, although phospho-R-Smad levels were initially stabilized by GSK3β and cyclin-dependent kinase inhibition.

Metabolism of methyleugenol in liver microsomes and primary hepatocytes: pattern of metabolites, cytotoxicity, and DNA-adduct formation.

Methyleugenol (1) is a constituent of many foods, in particular of herbal spices, and is used as flavoring agent in foodstuffs and as fragrance in cosmetics. 1 has been found to be carcinogenic in rodents, its metabolite, 1-hydroxymethyleugenol (2) acting as proximate DNA-binding carcinogen. We incubated 1 with liver microsomes of rat, bovine, and human origin.

Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling.

Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). While previous studies indicate that indirubin is a promising therapeutic agent for CML, the molecular mechanism of action of indirubin is not fully understood. We report here that indirubin derivatives (IRDs) potently inhibit Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells.

Genotoxic potential of methyleugenol and selected methyleugenol metabolites in cultured Chinese hamster V79 cells.

Methyleugenol is a substituted alkenylbenzene classified by the European Union's Scientific Committee on Food as a genotoxic carcinogen. We addressed cytotoxicity, genotoxicity and mutagenicity caused by methyleugenol and selected oxidative methyleugenol metabolites in Chinese hamster lung fibroblasts V79 cells. Cytotoxicity was measured by two cell proliferation assays, water soluble tetrazolium salt (WST) 1 and sulforhodamine B (SRB) assays.

N7-glycidamide-guanine DNA adduct formation by orally ingested acrylamide in rats: a dose-response study encompassing human diet-related exposure levels.

Acrylamide (AA) is formed during the heating of food and is classified as a genotoxic carcinogen. The margin of exposure (MOE), representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be of concern. After ingestion, AA is converted by P450 into the genotoxic epoxide glycidamide (GA).

Metabolism of methylisoeugenol in liver microsomes of human, rat, and bovine origin.

Methylisoeugenol (1,2-dimethoxy-4-propenylbenzene, 1) is a minor constituent of essential oils, naturally occurring as a mixture of cis/trans isomers. 1 is a U.S.

Biological effects of acrylamide after daily ingestion of various foods in comparison to water: a study in rats.

Scope: Acrylamide (AA), classified as a genotoxic carcinogen, is generated by heating foods. We studied whether the food matrix modulates bioavailability and/or biotransformation and investigated kinetics and biological effectiveness of AA in rats.

Methods And Results: AA was given to the animals at a daily intake level of AA containing foods for up to 9 days, resulting in an exposure of 50 or 100 μg AA/kg body weight (b.

Synthesis and cytotoxicity of novel indirubin-5-carboxamides.

Indirubins have been reported to act as potent inhibitors of protein kinases relevant to tumorigenesis and of tumor cell growth, but their development to antitumor drugs suffer from their poor water solubility. We synthesized a novel class of indirubin derivatives, indirubin-5-carboxamides, carrying amide substituents with basic centers. Quaternization or protonation of these alkylamino substituents provided indirubins with significantly improved solubility without loss of bioactivity.

Fate of 14C-acrylamide in roasted and ground coffee during storage.

Acrylamide (AA) is formed during heating of carbohydrate rich foods in the course of the Maillard reaction. AA has been classified as probably carcinogenic to humans. Storage experiments with roasted coffee have shown that AA levels decrease depending on storage time and temperature.

Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells.

Stat3 protein has an important role in oncogenesis and is a promising anticancer target. Indirubin, the active component of a traditional Chinese herbal medicine, has been shown previously to inhibit cyclin-dependent kinases, resulting in cell cycle arrest. Here, we show that the indirubin derivatives E564, E728, and E804 potently block constitutive Stat3 signaling in human breast and prostate cancer cells.

Intracellular localization of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine in membrane structures impeding the inhibition of cytosolic cyclic AMP-specific phosphodiesterase.

7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidino-pteridine (DC-TA-46) is a potent inhibitor of the rolipram-sensitive cAMP-specific phosphodiesterase isoenzyme family PDE4. DC-TA-46 inhibits cAMP-hydrolysis of PDE4 isolated from solid tumors of the human large cell lung tumor xenograft LXFL529 in the nanomolar range (IC(50)=16+/-5nM). Tumor cells, however, are growth inhibited only in the lower micromolar range as shown for the human large cell lung carcinoma cell line LXFL529L.