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PubMed1992

Synthesis and cytotoxicity of shikimate analogues. Structure:activity studies based on 1-crotonyloxymethyl-3R,4R,5R-trihydroxycyclohex-2-enone.

Syntheses are described for and structure:activity studies undertaken of the anti-tumour activity of (2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-+ ++enone) (1) and its analogues 1-crotonyloxymethyl-(3R,4S,5R)-3,4,5-trihydroxycyclohex-1-en e (3), 1-crotonyloxymethyl-(3R,4S,5S)-3,4,5-trihydroxycyclohexene (4) and 2-crotonyloxymethyl-2-cyclohexenone (5), which differ from 1 in the presence/absence of the cyclic keto group and/or the stereochemistry at one of the -OH bearing carbon atoms. None of the above compounds, including 1, directly inhibited glyoxalase I, isolated for the first time to homogeneity from rat Yoshida sarcomas and for which a purification protocol was developed. The apparent inhibition of glyoxalase I by 1 and 5 (but not detected for 4 or 3) could be explained by reaction of 1 and 5 with the glutathione present in the assay buffer and the consequent depletion of substrate. 1 and 5 were found to react readily with glutathione whereas 4 and 3 did not react. In vitro chemosensitivity studies against a panel of tumour cell lines of both mouse and human origin showed that in parallel with their thiol reactivity, 1 and 5 exhibited significant in vitro cytotoxicity whereas 4 and 3 did not. Concentrations of drug required to cause 50% cell kill (ID50 values) were in the range 0.5-19 microM (0.1-2.8 micrograms/ml) for 5, and 3-44 microM (0.7-10 micrograms/ml) for 1. The structural features causing the differences in antitumour effects were localized on this basis to the alpha,beta-unsaturated ketone linkage as opposed to the stereochemistry of the (trihydroxy) alcoholic sites.

Animals↗
PubMed1992

Pennyroyal oil toxicosis in a dog.

A dog was treated for fleas with the application of pennyroyal oil obtained by the owner at a health food store. Vomiting ensued within 2 hours, and despite emergency treatment, the dog died within 48 hours. At necropsy, pennyroyal oil was determined to be the cause of death.

Administration, Topical↗
PubMed2005

Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo.

We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 microg/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity.

Angiogenesis Inhibitors↗
PubMed2004

Soil activity and persistence of sulcotrione and mesotrione.

Greenhouse bioassays were set up using a small pot test method to determine the intrinsic sensitivity of different plant species to sulcotrione and mesotrione applied in a sandy loam soil. Herbicides were applied over an appropriate concentration range. After a 2-3 week test period, foliage fresh weight was determined. Data were subjected to a non-lineair regression analysis. Using the regression equations, ED50-values (herbicide concentrations that cause 50 percent foliage fresh weight reduction) were calculated for each combination of crop species and herbicide. To determine which replacement crops might be grown in case of failure of a crop treated with one of these herbicides, field persistence experiments were conducted over the 1993-2003 period for sulcotrione and the 1998-2003 period for mesotrione at the Experimental Farm, Biocentre Agri-Vet, Ghent University at Melle. Herbicides were applied in spring (about mid-March) on a bare soil; untreated control strips were included. Replacement crops were sown or planted approximately five weeks after herbicide applications. Visual estimations of crop injury were recorded at several intervals from sowing and fresh matter yield of plant parts was determined. Based on these data, crops were ranked according to their degree of sensitivity to either sulcotrione or mesotrione. Maize is very tolerant to both herbicides, although in some years, temporary injury could be seen in the field experiments. Italian rye-grass and fibre flax are tolerant crops; in field experiments a slight, temporary injury could be noticed in some years. Winter wheat displayed a high degree of tolerance to mesotrione (in both experiment types): however this crop was less tolerant to sulcotrione especially in the bioassay experiment. Based on its ED50-value, black salsify is tolerant to sulcotrione but under field conditions, the selectivity of this herbicide is quite variable; tolerance to mesotrione is moderate. Turnip and witloof chicory are clearly sensitive to mesotrione and sulcotrione whereas sugar beet, red clover and lettuce are extremely sensitive to both herbicides in both experiment types. Bioassays and field experiments provide a detailed and complete information about soil activity and persistence of both herbicides.

Belgium↗
PubMed1979

Microbiological transformations. XI. The use of immobilized Rhodotorula mucilaginosa cells to reduce some ketones.

Rhodotorula mucilaginosa cells were immobilized by polymerizing acrylamide with the addition of a cross-linked agent, a catalyst and an initiator. This gel was used for the stereospecific reduction of acetophenone and alpha-acetylnaphthalene resulting chromatographically pure alcohols with absolute configuration S. When karen-3-dion-2,5 was used as substrate, four products were obtained. Androstenolone was reduced with 30% yield. Activity of the immobilized cells could be regenerated by glucose.

Acetophenones↗
PubMed1992

Lactoferrin uptake by the rat liver. Characterization of the recognition site and effect of selective modification of arginine residues.

Recently it was found that lactoferrin, an iron-binding glycoprotein with a molecular weight of 76,500, inhibits the remnant receptor-mediated uptake of apolipoprotein E (apoE)-bearing lipoproteins by the liver. In the present study we characterized the hepatic recognition of lactoferrin. Intravenously injected 125I-lactoferrin was cleared rapidly from the circulation by the liver (92.8 +/- 9.5% of the dose at 5 min after injection). Parenchymal cells contained 97.1 +/- 1.5% of the hepatic radioactivity. Internalization, monitored by measuring the release of liver-associated radioactivity by the polysaccharide fucoidin, occurred slowly. Only about 40% of the liver-associated lactoferrin was internalized at 10 min after injection, and it took 180 min to internalize 90%. Subcellular fractionation indicated that internalized lactoferrin is transported to the lysosomes. Binding of lactoferrin to isolated parenchymal liver cells was saturable with a dissociation constant of 10 microM (20 x 10(6) binding sites/cell). The role of arginine residues on lactoferrin was studied by modifying these residues with 1,2-cyclohexanedione. The modification resulted in a strongly reduced liver association (15.9 +/- 1.6% of the dose at 5 min after injection). Furthermore, unlabeled 1,2-cyclohexanedione-modified lactoferrin did not inhibit the binding of 125I-lactoferrin to isolated parenchymal cells. Arginine residues on lactoferrin thus appear to be essential for its specific recognition by parenchymal liver cells. In particular the clustered N-terminal arginine residues, which resemble the arginine-rich receptor binding sequence in apoE, may be responsible for both the interaction of lactoferrin with its recognition site and the inhibition of the hepatic uptake of apoE-bearing lipoproteins.

Animals↗
PubMed2005

[Synthesis and character of megastigmatrienone].

In this synthetic route, the raw materials are obtained easily and the conditions of reactions are smoothly. The products in some main procedures of the route have high yieds. This synthetic route is a new way of the compound, there hasn't been reported anywhere. It needs further studies to be practically applied. According to this synthetic routes, the authors studied technolygical conditions of the reactions of every step. Some products are analyzed by refractive index, IR, HNMR, and MS and confirmed its structure.

Biological Products↗
PubMed1992

Alpha-isoenzyme of alcohol dehydrogenase from monkey liver. Cloning, expression, mechanism, coenzyme, and substrate specificity.

The cDNA for the alpha-isoenzyme from rhesus monkey (Macaca mulatta) liver was cloned and expressed in yeast. The alpha-isoenzymes of human and monkey liver alcohol dehydrogenase differ from the other human and horse liver enzymes in having Met57, Ala93, and Val116 instead of Leu57, Phe93, and Leu116 in the substrate binding pocket and Gly47 instead of Arg47 near the pyrophosphate moiety of the coenzyme. The effects of these differences on the kinetic mechanism, substrate specificity, and coenzyme binding were studied with the purified, recombinant monkey alpha-isoenzyme (MmADH alpha) and mutated enzymes with Gly47 substituted with His or Arg. The mechanism appears to be random for the binding of NAD+ and ethanol and ordered for NADH and acetaldehyde, with formation of a dead-end enzyme-NADH-ethanol complex. MmADH alpha reacts 130-fold slower (V/K) with ethanol and 3-25-fold slower with 2-methyl alcohols but 20-fold faster with cyclohexanol, as compared with horse (Equus caballus) liver EE isoenzyme (EqADH). MmADH alpha is stereoselective for the R isomer of 2-butanol, whereas EqADH favors the S isomer. Both enzymes have comparable reactivity with larger primary alcohols. MmADH alpha is more reactive with secondary alcohols and has highest activity with cyclohexanol. However, it does not react with steroids such as 5 beta-androstane-17 beta-ol-3-one. Molecular modeling suggests that the differences between MmADH alpha and EqADH are a result of the substitution of Ala for Phe93 and Thr for Ser48. MmADH alpha binds NAD+ most rapidly when a group with a pK of 7.4 is unprotonated, implicating His51 in this reaction. The G47R substitution decreased the dissociation constants for NAD+ and NADH and turnover numbers only about 2-fold, whereas the G47H substitution increased dissociation constants 7-14-fold and turnover numbers 4-fold. A basic residue at position 47 is not crucial for activity, as multiple interactions determine coenzyme affinity.

Alcohol Dehydrogenase↗
PubMed2005

Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-kappaB inhibitor.

The effects of the nuclear factor (NF)-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), combined with tumor necrosis factor (TNF)-alpha were evaluated in PK-8 pancreatic cancer cells. NF-kappaB was activated by TNF-alpha; however, the administration of DHMEQ abrogated its transcriptional activity. The addition of DHMEQ to TNF-alpha markedly induced apoptosis in PK-8 cells with down-regulation of anti-apoptotic c-FLIP and survivin. Combined treatment significantly suppressed cell viability in vitro, and the anti-tumor effect of DHMEQ was also significant in vivo. We investigated the apoptosis signaling pathway involved in these cell killing effects. Truncated Bid was produced by activated caspase-8, and the subsequent depolarization of the mitochondrial membrane potential (Delta Psi m) peaked at 6 h. Then, the activity of caspase-3 was up-regulated 8-fold. Z-VAD-fmk (a pan-caspase inhibitor) perfectly inhibited the up-regulation of caspase-3 but failed to reverse the cell viability. The above findings indicated that the growth inhibitory effect of combined treatment largely depended on mitochondria-associated caspase-independent apoptosis. The intracellular behavior of apoptosis-inducing factor (AIF) following depolarization of Delta Psi m suggested that AIF executed such a caspase-independent apoptosis. Interestingly, caspase-dependent apoptosis appeared within 6 h, whereas the caspase-independent apoptosis lagged. Thus, the addition of DHMEQ to TNF-alpha was capable of inducing caspase-independent apoptosis in pancreatic cancer cells. Once caspase-independent apoptosis was induced, the apoptosis demonstrated powerful cytotoxicity. Therefore, DHMEQ in combination with TNF-alpha may be a promising treatment for pancreatic cancer.

Apoptosis↗
PubMed2006

Survivin associates with cell proliferation in renal cancer cells: regulation of survivin expression by insulin-like growth factor-1, interferon-gamma and a novel NF-kappaB inhibitor.

Although survivin has been widely recognized as an attractive target for cancer therapy, the exact mechanism regarding the regulation of survivin and its effect on cell proliferation have yet to be clearly defined in renal cell carcinoma (RCC). We investigated herein the association between survivin expression and cell proliferation in a RCC cell line, KU19-20. In KU19-20 cells, cell proliferation and survivin expression were significantly induced by IGF-1, whereas they were inhibited by a novel NF-kappaB inhibitor dehydroxymethyl-epoxyquinomicin (DHMEQ) and IFN-gamma. The combination of DHMEQ and IFN-gamma inhibited cell proliferation synergistically with a pronounced attenuation of survivin expression. Furthermore, treatment with survivin-specific siRNA reduced expression of survivin and significantly inhibited cell proliferation. Survivin expression was thus associated with cell proliferation in KU19-20 cells. The regulation of survivin by IFN-gamma and/or an NF-kappaB inhibitor may therefore be a potential treatment modality for RCC.

Benzamides↗
PubMed2006

Antitumor effects of the novel NF-kappaB inhibitor dehydroxymethyl-epoxyquinomicin on human hepatic cancer cells: analysis of synergy with cisplatin and of possible correlation with inhibition of pro-survival genes and IL-6 production.

We tested the novel NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) in the hepatic cancer (HCC) HepG2, HA22T/VGH and HuH-6 cells. The sensitivity to the cell growth inhibitory and apoptotic effects of the agent increased along with the levels of constitutively activated NF-kappaB, which were low in HepG2 and higher in HA22T/VGH and HuH-6. In HA22T/VGH, DHMEQ exhibited synergy with cisplatin. In the same cells, DHMEQ exerted dose-dependent decreases in the nuclear levels of activated NF-kappaB and attenuated NF-kappaB activation by cisplatin. It down-regulated Bcl-XL mRNA in a dose-dependent manner and up-regulated that of Bcl-XS. It also decreased interleukin 6 (IL-6), NAIP and, after 16 h of exposure to the higher concentration tested (10 microg/ml), c-IAP-1 mRNA levels. At 10 microg/ml it caused significant increase in Bax, XIAP, cyclin D1 and beta-catenin mRNAs. The combination of DHMEQ with cisplatin produced unexpected significant decrease in c-IAP-2 and Bcl-XS mRNAs as well as additive decrease (IL-6, NAIP and, after 16 h, Bcl-XL) or increase (XIAP at 8 h) in gene expression. HA22T/VGH produce IL-6; in agreement with the results on mRNA, DHMEQ inhibited such a process. HA22T/VGH lack the IL-6 receptor alpha chain, ruling out that in these cells the antitumor effects of DHMEQ may be attributed to an interference with a growth stimulatory autocrine loop based on IL-6. However, the use of DHMEQ in HCC might be beneficial to contrast the adverse systemic effects of the released cytokine.

Antineoplastic Agents↗
PubMed2006

Chemical constituents of Glechoma longituba.

AIM: To study the chemical constituents of Glechoma longituba (Nakai) Kupr. METHODS: Manifold chromatography methods were used to separated the chemical constituents, and the chemical structures were determined by spectral analyses. RESULTS: Nine compounds were isolated from Glechoma longituba and identified, as: glecholone (1), 6R,9R-3-oxo-alpha-ionol (2), S(+)-dehydrovomifoliol (3), vomifoliol (4), corosolic acid (5), quercetin (6), stigmastenol (7), myristic acid (8) and triacontanol (9). CONCLUSION: Compound 1 is a new compound. Compounds 2 - 9 were isolated from this plant for the first time.

Cyclohexanones↗
PubMed2006

DHMEQ, a novel NF-kappaB inhibitor, induces apoptosis and cell-cycle arrest in human hepatoma cells.

Several reports have indicated that nuclear factor-kappaB (NF-kappaB) is constitutively activated in a variety of cancer cells including hepatoma cells and plays a key role in their growth and survival. Dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of an antibiotic epoxyquinomicin C is a novel NF-kappaB inhibitor. In the present study, we evaluated the effect of DHMEQ on the NF-kappaB activity in human hepatoma cells, Huh-7, HepG2 and Hep3B, and the anti-tumor effect of DHMEQ on these cells in vitro and in vivo. DHMEQ inhibited the steady-state transcriptional activity of NF-kappaB in all hepatoma cells. DHMEQ blocked the constitutive DNA-binding activity and TNF-alpha-mediated nuclear translocation of NF-kappaB in Huh-7 cells. DHMEQ (5-20 microg/ml) dose-dependently reduced the viable cell number of all hepatoma cells. DHMEQ (20 microg/ml) induced apoptosis in all hepatoma cells, especially in Hep3B cells, and cell-cycle arrest in Huh-7 and HepG2 cells. These effects were accompanied by downregulation of proteins involved in anti-apoptosis (Bcl-xL, XIAP or c-IAP2) and cell-cycle progression (cyclin D1), and induction of proteins involved in pro-apoptosis (Bax) and cell-cycle retardation (p21Waf1/Cip1), although the degree of changes by DHMEQ was different in each hepatoma cell type. Moreover, intraperitoneal administration of DHMEQ (8 mg/kg) significantly repressed the growth of Huh-7 tumor subcutaneously transplanted into BALB/c nu/nu athymic mice. Our results suggest that DHMEQ could qualify as a candidate for a new chemotherapeutic agent against human hepatoma.

Animals↗
PubMedDate not supplied

Novel 2-alkyl-1alpha,25-dihydroxy-19-norvitamin D3: efficient synthesis with Julia olefination, evaluation of biological activity and development of new analyzing system for co-activator recruitment.

New 2-alkyl-1alpha,25-dihydroxy-19-norvitamin D3 analogs were efficiently synthesized. The C2-alkyl-A-ring precursors were prepared as (3R,5R)-4-alkyl-3,5-dihydroxycyclohexanones from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The novel CD-ring coupling partner, with the elongated two carbon unit, was synthesized from 25-hydroxy Grundmann's ketone, and applied to modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were moderate (47-62%). After the separation of the diastereomers based on C2 stereochemistry using HPLC, the structure (2alpha or 2beta) was determined by 1H NMR studies including NOE (nuclear Overhauser effect) experiments. It was also found that 1H NMR chemical shifts on the A-ring showed good correlation with DeLuca's 2-methyl- and 2-ethyl-1alpha,25-dihydroxy-19-norvitamin D3 analogs. Among the synthesized 19-norvitamin D3 analogs, 2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxy-19-norvitamin D3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone (1), while its beta-isomer had only a 3% affinity. Both 2alpha-allyl- and 2alpha-propyl-1alpha,25-dihydroxy-19-norvitamin D3 and their 2beta-analogs possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1 and, interestingly, even the weaker ligand, 2beta-(3-hydroxypropyl)-1alpha,25-dihydroxy-19-norvitamin D3 (8b), showed a 6.7-fold higher potency in cell differentiation activity than that of 1. Next, a novel rapid analyzing system of ligand-induced co-factor recruitment on VDR was developed using fluorophore labelled CoA and HCHO fixing of the complex. The efficiency of recruitment of co-activators would explain the discrepancy between the biological activity and the VDR affinity of the ligand.

Alkylation↗
PubMed1975

Functional arginine residues involved in coenzyme binding by glutamate dehydrogenases.

Reaction of the NADP-dependent glutamate dehydrogenase of Neurospora with 1,2-cyclohexanedione results in a biphasic loss of enzyme activity. At the end of the rapid phase of the reaction (t1/2 = 1.5 min) the enzyme activity is diminished by approximately 60% with the simultaneous loss of 1 residue of arginine per subunit. After 60 min, the enzyme activity is completely lost with the modification of a total of 2 arginine residues per subunit. Reaction of bovine liver glutamate dehydrogenase with cyclohexanedione causes a rapid loss of approximately 45% of the enzyme activity and modification of about 1.5 residues of arginine per subunit. More prolonged treatment results in reaction of an additional 4 residues of arginine per subunit but is without further effect on the residual activity. The activity of the Neurospora enzyme is not protected by substrate, coenzyme, or a combination of both; however, the activity of the bovine enzyme is partially protected by high levels of NAD or NADP. Although the Km for alpha-ketoglutarate is unchanged by a limited modification of either enzyme with cyclohexanedione, the Km for coenzyme is increased about 2-fold for the Neurospora enzyme and about 1.5-fold for the bovine enzyme. The Ki of the Neurospora dehydrogenase for the competitive inhibitor 2'-monophosphoadenosine-5'-diphosphoribose is unchanged by the enzyme modification, but nicotinamide mononucleotide, a competitive inhibitor for the native Neurospora enzyme, does not inhibit the glutamate dehydrogenase with 1 modified arginine residue. This finding implies that the modified arginine is at or near the nicotinamide binding iste of the enzyme.

Amino Acids↗
PubMed2006

[New drugs; nitisinone].

Nitisinone is an inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase (4HPPD). Its rare area of use is hereditary tyrosinaemia, a life-threatening disease in which the last step in the catabolism of tyrosine cannot be taken due to the absence of an enzyme. The inhibition of 4HPPD, an enzyme that is active early in the catabolic cascade, prevents the accumulation of toxic metabolites of tyrosine.

Cyclohexanones↗