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PubMed2002

Molecular design and biological activities of NF-kappaB inhibitors.

NF-kappaB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. We designed a new NF-kappaB inhibitor that is based on the structe of the antibiotic epoxyquinomicin C. The designed compound, dehydroxymethyl-epoxyquinomicin (DHMEQ), inhibited the TNF-alpha-induced activation of NF-kappaB, and showed an anti-arthritic effect in mice. Recently, we looked into its mechanism of inhibition. DHMEQ inhibited the TNF-alpha-induced cellular DNA binding of nuclear NF-kappaB, but not the phosphorylation or degradation of I-kappaB. Moreover, DHMEQ inhibited the TNF-alpha-induced nuclear accumulation of p65, a component of NF-kappaB. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and the large T antigen. Also, it did not inhibit the TNF-alpha-induced activation of JNK, but synergistically induced apoptosis with TNF-alpha in human T cell leukemia Jurkat cells. Therefore, DHMEQ specifically inhibited the NF-kappaB-activating pathway in the TNF-alpha-treated cells. Taken together, our data show that DHMEQ is a unique inhibitor of NF-kappaB that acts at the level of the nuclear translocation. It may be useful as an anti-inflammatory and anticancer agent.

Animals↗
PubMed2003

Suppression of hormone-refractory prostate cancer by a novel nuclear factor kappaB inhibitor in nude mice.

We have synthesized and explored the feasibility of using a novel nuclear factor (NF) kappaB inhibitor, a dehydroxymethylepoxyquinomicin designated as DHMEQ, against prostate cancer. The activity of NFkappaB, evaluated by transient transfection of a luciferase reporter DNA containing a specific binding sequence for NFkappaB, was inhibited by DHMEQ in three human hormone-refractory prostate cancer cell lines, DU145, JCA-1, and PC-3. Statistically significant growth inhibition was achieved by 20 micro g/ml of DHMEQ, and marked levels of apoptosis were induced 48 h after DHMEQ administration in vitro. Electrophoretic mobility shift assay showed that DHMEQ completely inhibited NFkappaB DNA binding activity in JCA-1 cells. Furthermore, i.p. administrations of DHMEQ significantly inhibited pre-established JCA-1 s.c. tumor growth in nude mice without any side effects. Our result indicates the possibility of using a novel NFkappaB activation inhibitor, DHMEQ, as a new treatment strategy against hormone-refractory prostate cancer.

Animals↗
PubMed2002

[Studies on water-soluble constituents of Echinacea prupurea].

AIM: To study the water-soluble constituents of Echinacea purpurea. METHODS: The compounds were isolated by chromatography method and their structures were identified on the basis of spectral analyses. RESULTS: Five compounds were identified as 2-(4-hydroxylphenyl)-ethyl-O-alpha-L-rhamnopy-ranoasyl-(1-->6)-beta-D- glucopyranoside, named echipuroside A 1); (6S, 9R)-6-hydroxy-3-one-alpha-inonol-9-O-beta-D-glucopyranoside 2), ampelopsisionoside 3); phenylmethyl-6-O-beta-D-xylopyranosyl(1-->6)-beta-D-glucopyranoside 4) and phyenylmethyl-beta-D-glucopyranoside 5). CONCLUSION: Compound 1 is a new compound, the others were isolated from this plant for the first time.

Cyclohexanones↗
PubMed2002

Soil persistence of 4-HPPD-inhibitors in different soil types.

In field experiments carried out during the 1997-2001 period on four different soil types (sand, sandy loam, heavy sandy loam and clay) in Flanders (Belgium), the persistence of the three 4-HPPD inhibiting maize herbicides mesotrione (100 and 150 g ha-1), sulcotrione (300 and 450 g ha-1) and isoxaflutole (75 and 125 g ha-1) was studied. Therefore, soil samples were taken at regular intervals from application in spring and frozen. When all samples had been taken, greenhouse bioassays were set up to detect herbicide residues in the different soil types. Therefore, two extremely sensitive test plants, sugarbeet (Beta vulgaris L. spp. altissima Doell. var. saccharifera Deck.-Dill) and red clover (Trifolium pratense L.) were sown in the soil samples. Test plants were harvested after 2 (sugarbeet) and 3 (red clover) weeks and foliage fresh weight per plant was determined. This parameter was expressed relatively to the average fresh weight per plant of the plants sown in the control soil samples taken at each sampling date. The bioassays revealed several factors that influence the persistence of the herbicide tested. First, there is a remarkable influence of the experimental year due to variation in weather conditions (especially rainfall and temperature during the first weeks after spraying). Secondly, a different soil texture results in a highly different persistence: the shortest biological persistence was noticed each year in clay, followed by heavy sandy loam; the longest persistence was recorded in sandy and sandy loam soil types. Thirdly, there are important differences between the three herbicides tested: isoxaflutole (a member of the isoxazole chemical family) was shown to be less persistent than sulcotrione and mesotrione (both members of the triketone family). Remarkably, this was not the case in clay, where a longer persistence could be seen for isoxaflutole compared to sulcotrione and mesotrione. This study also revealed that applying a low rate results in a shorter persistence period compared to the higher rate. All these factors work together in a complex way which determines the persistence of the three herbicides tested.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2003

Reversibility of cirrhotic regenerative liver nodules upon NTBC treatment in a child with tyrosinaemia type I.

UNLABELLED: In a male patient with hereditary tyrosinaemia type I (HTI), NTBC [2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexandion] treatment and a diet low in phenylalanine and tyrosine were started at the age of 4 wk. At the recommended average dosage (1 mg kg(-1)), liver failure improved transiently. After 4 mo of treatment, with increased body weight, the dose had decreased to 0.7 mg kg(-1), and diffuse cirrhotic changes in liver parenchyma and multiple nodules were visualized by ultrasonography. Multiple nodules in the liver parenchyma were differentiated from hepatocellular carcinoma by magnetic resonance imaging (MRI) using mangafodipir trisodium as a paramagnetic liver-specific contrast agent. Augmentation of NTBC dosage resulted in a decrease in serum alpha-fetoprotein levels and in significant regression of liver nodules on MRI. CONCLUSION: In HTI patients with a poor response to NTBC treatment and/or development of cirrhotic changes of liver parenchyma, augmentation of the recommended NTBC dosage may result in significant improvement of symptoms.

Cyclohexanones↗
PubMed2003

Preparation of radioactively labeled dehydroxymethyl-epoxyquinomicin, an NF-kappa B function inhibitor.

Dehydroxymethylepoxyquinomicin (DHMEQ), a synthetic derivative of epoxyquinomicin C, is a potent and specific inhibitor of NF-kappa B in cultured cells. Tritium-labeled DHMEQ was synthesized with sodium borotritium. Specific radioactivity of the synthesized tritium-labeled DHMEQ was 15.45 mCi/mmol. This compound would be for the study of the mechanism of action and the stability of DHMEQ.

Benzamides↗
PubMedDate not supplied

Identification of the antibiotic hops component, colupulone, as an inducer of hepatic cytochrome P-4503A in the mouse.

A higher level of cytochrome P-450 (P450)-dependent ethylmorphine (EM) N-demethylase activity was observed in hepatic microsomes from mice fed a natural-ingredient diet ("crude diet") than in those from mice fed a semi-purified diet ("purified diet"). This led to the testing of individual ingredients of the crude diet as inducers of the P-450 system. Brewers yeast proved to be the most significant inductive component of the crude diet. Further investigation revealed that hop components (lupulones) absorbed on yeast during the brewing process were responsible for the induction of the P-450 system. The induction of P-450 and several P-450-dependent monooxygenase activities (EM N-demethylation, aniline hydroxylation, benzo[a]pyrene hydroxylation) by colupulone with respect to dose and time course were investigated. The very large increase in EM N-demethylase activity elicited by colupulone suggested that P-4503A had been induced. Western blot technology verified this speculation. Western blot analysis of microsomal protein from mice fed hops, brewers yeast, or the residue of a hexane extract of hops supported the conclusion that all of these substances induced P-4503A. These substances were also relatively good inducers of P-4502B, but not as inductive of this isozyme as the crude diet. This is interpreted to mean that not all of the inductive properties of the crude diet are due to hop components. These studies question the use of crude commercial diets in studies of P-450 systems. They may also challenge some current definitions of "constitutive" and "induced" P-450s.

Animals↗
PubMed1992

Synthesis of condensed heterocycles from 3-aryl-2,4-dicarbethoxy-5-methylcyclohexanones and their testing for antimicrobial activity.

Condensation of the title compounds (1) with hydroxylamine hydrochloride, hydrazines and/or aromatic amines resulted in the formation of the benzisoxazoles 2, oximes 3, indazolines 4 and beta-keto anilides 6. The oxime derivatives and anilides underwent cyclization to compounds 2. The interaction between 1 and thiourea gave the benzothiazines 7 and thiouracils 8. Compounds 8 on treatment with monochloroacetic acid gave the dioxo compounds 9, while their reaction with hydrazine hydrate afforded the hydrazino derivatives 10, which upon treatment with nitrous acid gave the azido or tetrazolo derivatives 11 and 12. Treatment of 1 with 2,3-diaminopyridine and/or 2-amino-3-hydroxy-pyridine gave the pyrimidoquinazolines 13 or 14. Some of the synthesized compounds were screened to test their antimicrobial properties.

Anti-Bacterial Agents↗
PubMed2004

[Mode of action and molecular target of ECH, a specific inhibitor of death receptor-dependent apoptosis].

ECH (epoxycyclohexenone) specifically blocks death receptor-mediated apoptosis induced by anti-Fas antibody, Fas ligand, or TNF-alpha, whereas it has no effect on death receptor independent apoptosis induced by staurosporine, MG-132, C2-ceramide, or UV irradiation. ECH blocks the activation of pro-caspase-8 in the death-inducing signaling complex (DISC), even though recruitment of FADD and pro-caspase-8 is not affected. In Fas ligand treated cells, ECH is only able to inhibit the activation of pro-caspase-8 and it has no effect on the already-activated caspase-8. ECH has a relatively higher affinity to pro-caspase-8, although it directly binds both pro- and active-form of caspase-8. In conclusion, ECH targets pro-caspase-8 and blocks the self-activation of pro-caspase-8 in the DISC, and thus selectively inhibits death receptor-mediated apoptosis. Moreover novel non-peptide inhibitors, RKTS-33 & RKTS-34 that are chemically synthesized derivatives of ECH have been developed.

Apoptosis↗