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At least 685 records · Page 38Linked to original sources
PubMed2004

DM27, an enaminone, modifies the in vitro transport of antiviral therapeutic agents.

OBJECTIVE: For most antiviral drugs, low or variable bioavailability is attributed to poor absorption, susceptibility to efflux, or first pass metabolism. Enaminones are beta dicarbonyl compounds, which display P-glycoprotein (P-gp) substrate properties with high efflux ratios. This study investigates the influence of DM27, an enaminone, on the in vitro transport of antiviral agents and the possibility of using DM27 as a P-gp inhibitor to prevent the efflux of certain antiretroviral agents. METHODS: The transport of [3H]amprenavir, [3H]saquinavir, [3H]ritonavir, [14C]zidovudine (AZT) and [3H]acyclovir was evaluated across Caco-2 cells with DM27 (10(-10)-10(-4) M). In addition, the effect of DM27 (10(-6) M) on the transport of transcellular and paracellular markers was tested to evaluate its influence on these transport pathways. The apparent permeability coefficient (Papp) for each drug or marker was calculated with/without DM27 and toxicity evaluation for DM27 was performed using the MTS assay. RESULTS: The mean Papp for the investigated antiviral agents significantly increased by 22%-51% after DM27 incubation without any toxicity to the Caco-2 cells. In addition, DM27 did not influence the transcellular or paracellular transport of propranolol and mannitol, respectively. CONCLUSIONS: DM27, an enaminone, increased the transport of antiretroviral drugs and acyclovir in a nontoxic manner without affecting the paracellular or transcellular transport of these drugs. This study suggests that DM27 may be used as a P-gp efflux inhibitor to enhance the oral bioavailability of antiviral drugs and that drug-drug interactions will most probably be encountered upon co-administration of P-gp substrate drugs with enaminones.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Application of in vivo bioluminescence to the study of ionophoretic action.

Ionophores (carbonyl cyanide m-chlorophenylhydrazone; valinomycin; and the hop-derived compounds colupulone, trans-isohumulone and trans-humulinic acid) reduced the rate of dodecanal-dependent light emission from IuxA/B-transformed cells of Lactococcus lactis subsp. diacetylactis F712 when the cells were suspended in a buffered medium (pH 6.4) containing glucose. This allowed an assay for ionophores to be devised and permitted measurement of the effects of such compounds on the test organism by the use of a non-destructive technique in real time.

Anti-Bacterial Agents↗
PubMed2004

In situ product removal using a crystallization loop in asymmetric reduction of 4-oxoisophorone by Saccharomyces cerevisiae.

In situ product crystallization was investigated for solid product crystals that were obtained during fermentation. The model reaction was the asymmetric reduction of 4-oxoisophorone (OIP) using baker's yeast (S. cerevisiae) as a biocatalyst. The target product was 6R-dihydro-oxoisophorone (DOIP), also known as levodione, a key intermediate in carotenoid synthesis. DOIP was degraded by baker's yeast mainly to (4S,6R)-actinol, an unwanted byproduct in the process. Actinol formation reached up to 12.5% of the initial amount of OIP in the reactor during a batch process. However, better results were obtained when the dissolved DOIP concentration was controlled using an integrated fermentation-crystallization process because: (a) actinol formation was reduced to 4%; and (b) DOIP crystal formation in the reactor was avoided. DOIP productivity was improved by 50% and its selectivity was raised from 87% to 96% relative to the batch process. In the integrated process, most of the product was recovered as pure crystals; this may already minimize, if not eliminate, the need for organic solvents in the final purification steps. An almost sixfold reduction in biocatalyst consumption per kilogram product was achieved, which also can contribute to the minimization of waste streams.

Biotransformation↗
PubMedDate not supplied

Simple determination of formaldehyde in dimedone adduct form in biological samples by high performance liquid chromatography.

A high performance liquid chromatographic method for the determination of endogenous formaldehyde in dimedone adduct form in biological samples is described. The simple procedure involves extraction of the formaldehyde of different binding force in biological samples with methanol containing dimedone as the capture molecule and separation on a C18 reversed phase column with methanol as eluent.

Animals↗
PubMed2007

A comparative analysis of the sugar phosphate cyclase superfamily involved in primary and secondary metabolism.

Sugar phosphate cyclases (SPCs) catalyze the cyclization of sugar phosphates to produce a variety of cyclitol intermediates that serve as the building blocks of many primary metabolites, for example, aromatic amino acids, and clinically relevant secondary metabolites, for example, aminocyclitol/aminoglycoside and ansamycin antibiotics. Feeding experiments with isotopically labeled cyclitols revealed that cetoniacytone A, a unique C(7)N-aminocyclitol antibiotic isolated from an insect endophytic Actinomyces sp., is derived from 2-epi-5-epi-valiolone, a product of SPC. By using heterologous probes from the 2-epi-5-epi-valiolone synthase class of SPCs, an SPC homologue gene, cetA, was isolated from the cetoniacytone producer. cetA is closely related to BE-orf9 found in the BE-40644 biosynthetic gene cluster from Actinoplanes sp. strain A40644. Recombinant expression of cetA and BE-orf9 and biochemical characterization of the gene products confirmed their function as 2-epi-5-epi-valiolone synthases. Further phylogenetic analysis of SPC sequences revealed a new clade of SPCs that might regulate the biosynthesis of a novel set of secondary metabolites.

Amino Acid Sequence↗
PubMed2005

Neolignan and megastigmane glycosides from the leaves of Pterospermum semisagittatum.

Three compounds namely, (7S,8R)-dihydrodehydrodiconiferyl alcohol-9'-O-beta-D-glucopyranoside (1), 10-hydroxy-4,7-megastigmadien-3-one-9-O-beta-D-glucopyranoside (2) and 9-hydroxy-4,7-megastigmadien-3-one-10-O-beta-D-glucopyranoside (3) were isolated from the methanol extract of Pterospermum semisagittatum. The structures of these compounds were elucidated by spectroscopic methods. While glycosides 2 and 3 appear to be new, this is the third report of isolation of compound 1 from any natural source.

Cyclohexanones↗
PubMed2001

Enantioconvergent synthesis of (-)-(S)- and (+)-(R)-2-acetyl-3,6-dihydroxycyclohex-2-enone starting from rac-6-hydroxy-3-methoxycyclohex-2-enone.

The synthesis of enantiomerically pure (-)-(S)- and (+)-(R)-2-acyl-3,6-dihydroxycyclohex-2-enone starting from diastereomerically pure N-tosyl-(S)-proline esters 3-methoxy-6-hydroxycyclohex-2-enone 1 is presented. An enantioconvergent synthesis of either (-)-(S)- and (+)-(R)-2-acyl-3,6-dihydroxycyclohex-2-enone starting with the racemic alpha-ketol 1 through a conversion of ( approximately 1:1) mixture of diastereomeric esters into one diastereomer by a repeated crystallization, followed by dimethylaminopyridine-catalyzed equilibration as key steps is described.

Cyclohexanols↗
PubMed2005

C-H...O hydrogen bonds in cyclohexenone reveal the spectroscopic behavior of Csp3-H and Csp2-H donors.

C-H...O hydrogen bonds in liquid 2-cyclohexen-1-one are studied to assess the vibrational spectroscopic behavior of the Csp2-H and Csp3-H donors. The presence of a pseudo-isosbestic point in the vC = O region supports the assignment of the two observed bands to two species in equilibrium, considered to be the free and 1:1 associated forms. The values of deltaH degrees =-18.5 +/- 0.6 kJmol(-1) and deltaS degrees = -76 +/- 2 J K(-1) mol(-1) for the dimerization through C-H...O hydrogen bonds were obtained from the dimerization constant at different temperatures. The concentration-dependent intensity of the vCH2 band profile is ascribed to the presence of a blue-shifted band from the hydrogen-bonded Csp3-H group. However, the most surprising result is the absence of concentration- or temperature-dependent intensities in the bands assigned to the stretching modes of the Csp2-H donors.

Carbon↗
PubMed2006

Effects of a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on growth, apoptosis, gene expression, and chemosensitivity in head and neck squamous cell carcinoma cell lines.

BACKGROUND: Recent studies provide evidence that the constitutive activation of nuclear factor-kappa B, NF-kappaB plays a critical role in enhancing the growth of several types of malignancies, including head and neck squamous cell carcinoma (HNSCC). METHODS: In this study, we examined the effects of a newly synthesized NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on growth, induction of apoptosis, gene expression, and chemosensitivity in two HNSCC cell lines (YCU-H891 and KB), which expressed high levels of nuclear NF-kappaB protein. RESULTS: DHMEQ showed strong growth inhibitory effects on these two cell lines, with a 50% cell growth inhibition (IC50) concentration of approximately 20 microg/mL. These growth inhibitory effects were associated with inhibition of the NF-kappaB activity. Treatment with DHMEQ induced apoptosis in a dose-dependent manner accounting, at least in part, for the growth inhibition by DHMEQ. DHMEQ strongly inhibited cyclin D1 and vascular endothelial growth factor (VEGF) promoter activity and decreased the levels of cyclin D1 protein and VEGF mRNA in KB cells. In addition, low concentrations of DHMEQ (1.0 or 5.0 microg/mL) synergistically enhanced the cellular sensitivity of YCU-H and KB cells to cisplatin, which is a key chemotherapeutic agent in the treatment of HNSCC. CONCLUSIONS: These results suggest that DHMEQ may be effective when used alone or in combination with other agents in the treatment of HNSCC.

Apoptosis↗
PubMed2004

Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death.

The murine model of hereditary tyrosinemia type 1 (HT1) was used to analyze the relationship between chronic liver disease and programmed cell death in vivo. In healthy fumarylacetoacetate hydrolase deficient mice (Fah(-/-)), protected from liver injury by the drug 2-(2- nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), the tyrosine metabolite homogentisic acid (HGA) caused rapid hepatocyte death. In contrast, all mice survived the same otherwise lethal dose of HGA if they had preexisting liver damage induced by NTBC withdrawal. Similarly, Fah(-/-) animals with liver injury were also resistant to apoptosis induced by the Fas ligand Jo-2 and to necrosis-like cell death induced by acetaminophen (APAP). Molecular studies revealed a marked up-regulation of the antiapoptotic heat shock proteins (Hsp) 27, 32, and 70 and of c-Jun in hepatocytes of stressed mice. In addition, the p38 and Jun N-terminal kinase (JNK) stress-activated kinase pathways were markedly impaired in the cell-death resistant liver. In conclusion, these results provide evidence that chronic liver disease can paradoxically result in cell death resistance in vivo. Stress-induced failure of cell death programs may lead to an accumulation of damaged cells and therefore enhance the risk for cancer as observed in HT1 and other chronic liver diseases.

Acetaminophen↗
PubMed2005

A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo.

Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.

Animals↗
PubMed1986

Elevation of intracellular glutathione content associated with mitogenic stimulation of quiescent fibroblasts.

The relationship between total glutathione (GSH) content and cell growth was examined in 3T3 fibroblasts. The intracellular GSH level of actively growing cultures gradually decreases as these cells become quiescent by either serum deprivation or high cell density. Upon mitogenic stimulation of sparse, quiescent (G0/G1) cultures with serum, there is a rapid 2.3-fold elevation in intracellular GSH levels which is maximal by 1 h and returns to baseline by 2 h. This is followed by a more gradual increase in GSH content as cells enter the S phase. In addition, the elevation in GSH content is required for maximum induction of DNA synthesis. Treatments that prevent the early increase in intracellular GSH levels do not affect protein synthesis but result in a reversible dose-dependent decrease in the percent of cells capable of entering S phase. These results indicate that GSH may be important in the regulation of cellular proliferation.

Animals↗
PubMed1991

Age-related acute depletion of cerebral glutathione by peroxidative stress.

Cyclohexene-1-one and cycloheptene-1-one cause a severe age-related depletion of reduced glutathione (GSH) in the forebrain of 5- or 15- or 25-month-old rats. Chronic pretreatment with phosphatidylcholine partially inhibits the GSH depletion in old forebrains by the prooxidants tested, suggesting that in aged animals alterations in mitochondrial inner membrane phospholipid composition and/or cytochrome oxidase activity might play a role in oxygen free-radical production.

Aging↗
PubMed1975

Reduction of cycloalkanones by Aspergillus niger.

The mould Aspergillus niger was grown in a carefully established culture medium containing one of the following test substrates: cyclopentanone, -hexanone, -heptanone, and their 2-substituted methyl derivatives. Growth curves, glucose consumption curves and curves showing the course of the oxido-reduction reaction are given.

Aspergillus↗
PubMed2001

Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants.

Previous in vitro studies evaluating the permeability of enaminones suggested that their blood-brain barrier (BBB) transport might be influenced by the presence of an efflux mechanism. Therefore, transport mechanisms responsible for these anticonvulsants across the BBB were examined. The transport of enaminones (1 x 10(-4) M) were evaluated over 120 min with verapamil (50 microM) and probenecid (100 microM) using bovine brain microvessel endothelial cells (BBMECs) to assess the role of multidrug resistant (MDR) transport proteins [i.e., P-glycoprotein (Pgp) and MDR protein 1 (MRP1)] on efflux, respectively. Uptake studies in the presence and absence of rhodamine 123 (R123; 3.2 and 5.0 microM) were also performed in a Pgp overexpressing cell line, MCF-7/Adr. Select enaminone esters (12.5 mg/kg) were administered intravenously to mdr 1 a/b (+/+), mdr 1 a/b (-/-) knockout and probenecid pretreated mice (20 +/- 5g). Enaminones and R123 were assayed with validated ultraviolet and fluorescence high-performance liquid chromatography methods, respectively. Verapamil and probenecid significantly ( p>0.05) inhibited the transport of select enaminone esters across BBMECs. Two enaminones caused a statistically significant increase in the uptake of R123 in MCF-7/Adr cells. Concentrations of select enaminones in mdr 1 a/b (-/-) mice brains were significantly higher ( p<0.05) compared with those in mdr 1 a/b (+/+) mice brains; however, no differences were observed in probenecid pretreated animals. Taken together, these results strongly suggest that Pgp may influence enaminone transport at the BBB and hence affect epilepsy treatment with these agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗