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PubMed1991

Diacylglycerol lipase and the contractile action of epidermal growth factor-urogastrone: evidence for distinct signal pathways in a single strip of gastric smooth muscle.

In guinea pig gastric longitudinal muscle preparations, wherein epidermal growth factor-urogastrone (EGF-URO) causes contraction via the generation of arachidonate-derived prostaglandins, the specific diacylglycerol lipase (DG lipase) inhibitor, U57,908 (formerly designated RHC 80267) completely blocked EGF-URO and transforming growth factor-alpha (TGF-alpha)-mediated contraction, without affecting contractions caused by other agonists such as bradykinin, prostaglandin F2 alpha or arachidonic acid (AA). In contrast, the contractile actions of EGF-URO and TGF-alpha on the gastric circular muscle component, present in the same tissue strip as the longitudinal muscle preparation, were unaffected by concentrations of U57,908 that maximally inhibited contraction in the longitudinal muscle preparation. We conclude that in the longitudinal muscle preparation, EGF-URO acts not by the activation of phospholipase A2, but rather via the metabolism of diacylglycerol by DG lipase, thereby liberating arachidonic acid for the synthesis of contractile prostanoids. We also conclude that, even in the same tissue, the effects of EGF-URO on anatomically different components (longitudinal muscle versus circular muscle) can be mediated via two quite distinct signal transduction pathways.

Animals↗
PubMed1991

Studies of conformation and interaction of the cyclohexenone and acetyl group of progesterone with liposomes.

The conformations of the A-ring and the 17-acetyl groups of progesterone were examined within liposomes, which were prepared from L-alpha-phosphatidylcholine in the presence or absence of cholesterol in the buffer, using qualitative nuclear magnetic resonance and circular dichroism of the progesterone spectra in the wavelength regions of 260-360 nm. The preferred conformational assignments, in the rotational conformations of the 17-acetyl group and invertible conformations of the cyclohexenone of progesterone were discussed on the basis of the elliptical strength of the Cotton effect and an energy estimation of the preferred conformers. Energetically unstable conformers of the acetyl group and alpha,beta-unsaturated cyclohexenone of progesterone remarkably increased with an increase in the concentration of the liposomes. The liposomes containing 10% cholesterol were similar to the effect of the liposomes lacking cholesterol on the 17-acetyl group and the alpha,beta-unsaturated cyclohexenone but those containing 50% cholesterol showed an increase in the number of energetically stable conformers of the alpha,beta-unsaturated cyclohexenone. The nuclear magnetic resonance signal from liposomes together with the progesterone indicated the existence of the progesterone adjacent to a double bond or ester moiety in the lipid molecule. Therefore, it was apparent that the liposomes and the cholesterol within the liposomes regulated the conformational populations of both the cyclohexone and acetyl groups of the progesterone molecule.

Cholesterol↗
PubMed1995

A new procedure for the labeling of peptides and amino acids.

Several stable, water soluble cyclohexa-2,4-dien-1-ones have been prepared and their photolytic coupling reactions in aqueous solution at 28 degrees C with various amino acids and dipeptides investigated. This procedure represents a new and high yielding method for the labeling of the terminal amino functionality of peptides and amino acids.

Amino Acids↗
PubMed1994

Reduction of bicyclo[3.3.1]nonane-2,8-diones with baker's yeast.

Reduction of bicyclo[3.3.1]nonane-2,8-dione (1) and its homologues 2 and 3 with baker's yeast affords (1R,5S,8S)-8-hydroxybicyclo[3.3.1]nonan-2-one (4) and its higher homologues 5 and 6 with ca 97% e.e. in 72-86% yields. The absolute configuration of 5 was confirmed by the X-ray crystallographic analysis of its camphanic ester 22.

Bridged Bicyclo Compounds↗
PubMed2005

Tandem mass spectrometric assay of succinylacetone in urine for the diagnosis of hepatorenal tyrosinemia.

We describe an isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of succinylacetone (SA) in urine for the diagnosis of hepatorenal tyrosinemia (HT1). The method used 15N-labeled 5(3)-methyl-3(5)-isoxazole propionic acid as internal standard. Urine samples were oximated with hydroxylamine hydrochloride at 80 degrees C, extracted by solvent-solvent extraction, and followed by derivatization of the butyl ester. The butylated isoxazole derivatives of SA and its internal standard were detected and quantified using positive ion electrospray LC-MS/MS with selected reaction monitoring. The turnaround time between injections was 10 min. Calibration curves were linear over the range of 0.0633-63.3 micromol/L. The intra- and interday assay variations were less than 7%. Mean recoveries of SA at three different concentrations ranged from 96 to 109%. During the course of this study, we identified 12 new patients with HT1 and applied this method to follow up the treatment of 4 of these patients as well as previously diagnosed HT1 patients.

Adolescent↗
PubMed2005

Spectroscopic and computational studies of NTBC bound to the non-heme iron enzyme (4-hydroxyphenyl)pyruvate dioxygenase: active site contributions to drug inhibition.

(4-Hydroxyphenyl)pyruvate dioxygenase (HPPD) is an alpha-keto-acid-dependent dioxygenase which catalyzes the conversion of (4-hydroxyphenyl)pyruvate (HPP) to homogentisate as part of tyrosine catabolism. While several di- and tri-ketone alkaloids are known as inhibitors of HPPD and used commercially as herbicides, one such inhibitor, [2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione (NTBC), has also been used therapeutically to treat type I tyrosinemia and alkaptonuria in humans. To gain further insight into the mechanism of inhibition by NTBC, a combination of CD/MCD spectroscopy and DFT calculations of HPPD/Fe(II)/NTBC has been performed to evaluate the contribution of the Fe(II)-NTBC bonding interaction to the high affinity of this drug for the enzyme. The results indicate that the bonding of NTBC to Fe(II) is very similar to that for HPP, both involving similar pi-backbonding interactions between NTBC/HPP and Fe(II). Combined with the result that the calculated binding energy of NTBC is, in fact, approximately 3 kcal/mol less than that for HPP, the bidentate coordination of NTBC to Fe(II) is not solely responsible for its extremely high affinity for the enzyme. Thus, the pi-stacking interactions between the aromatic rings of NTBC and two phenyalanine residues, as observed in the crystallography of the HPPD/Fe(II)/NTBC complex, appear to be responsible for the observed high affinity of drug binding.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2006

Antitumor quinols: role of glutathione in modulating quinol-induced apoptosis and identification of putative cellular protein targets.

Novel heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) are promising novel anticancer agents. They exhibit in vitro antiproliferative activity against colon, renal, and breast carcinoma cell lines as well as in vivo antitumor activity in colon, renal, and breast tumor xenografts. Elucidation of the mechanism of antitumor action of these compounds is of great importance. We show in this study that the compounds induced apoptosis as demonstrated by caspase 3 and PARP cleavage at doses causing G(2)/M cell cycle arrest. Glutathione was found to play an important role in modulating quinol-mediated cytotoxicity. In HCT 116 cells, treatment with 1 and 2 caused a 2- to 3-fold increase in the total glutathione content, suggestive of a glutathione-mediated antioxidant response. Indeed, buthionine sulfoximine (BSO)-induced glutathione depleted cells were 6-10 times more sensitive to 1 and 2, while glutathione monoethyl ester supplementation decreased the antitumor potencies by 2-3 times. In further studies we determined other cellular proteins which bind to an immobilized quinol analog, and identified several proteins including beta-tubulin, heat shock protein 60, and peroxiredoxin 1 as potential molecular targets of quinols that may contribute to their proapoptotic and antiproliferative effects.

Antineoplastic Agents↗
PubMed2006

Evaluation of dichloroacetate treatment in a murine model of hereditary tyrosinemia type 1.

Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease severely affecting liver and kidney and is caused by a deficiency in fumarylacetoacetate hydrolase (FAH). Administration of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) improves the HT1 phenotype but some patients do not respond to NTBC therapy. The objective of the present study was to evaluate whether administration of dichloroacetate, an inhibitor of maleyl acetoacetate isomerase (MAAI) to FAH-knockout mice could prevent acute pathological injury caused by NTBC withdrawal. DCA (0.5 and 5g/L) was given in combination with a standard diet or with a tyrosine-restricted diet. With the low-tyrosine diet body weight loss and most of hepatic and renal injuries were prevented regardless the DCA dose. The administration of DCA with a standard diet did not prevent damage nor the oxidative stress response nor the AFP induction seen in FAH-knockout mice. DCA was shown to inhibit hepatic MAAI activity to 86% (0.5g/L) and 94% (5g/L) of untreated wild-type mice. Interestingly, FAH(-/-) mice deprived of NTBC (NTBC-OFF) and NTBC-treated FAH-knockout mice had similar low hepatic MAAI activity levels, corresponding to 10-20% of control. Thus the failure of DCA treatment in FAH(-/-) mice seems to be attributed to the residual MAAI activity, high enough to lead to FAA accumulation and HT1 phenotype.

Animals↗
PubMed2005

Inhibition of inflammatory cytokine secretion from mouse microglia cells by DHMEQ, an NF-kappaB inhibitor.

Activation of microglia has been implicated in various neurodegenerative disorders, and thus the inhibition of microglial activity may suppress these disorders. Earlier we designed and synthesized an NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) that showed anti-inflammatory and anti-tumor activities in vivo. In the present research, we studied whether DHMEQ would inhibit the activation of mouse microglial cells. DHMEQ inhibited lipopolysaccharide (LPS)-induced activation of NF-kappaB in an electrophoresis mobility shift assay. It also inhibited LPS-induced secretions of TNF-alpha and IL-6 from mouse microglial cell line 6-1 cells.

Animals↗
PubMed2006

Inhibition of macrophage activation and phagocytosis by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin.

Previously, we designed and synthesized a new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). In the present research we looked into the effect of DHMEQ on the activation of macrophages, especially on the phagocytotic activity of cells of the mouse macrophage-like cell line RAW264.7. DHMEQ inhibited lipopolysaccharide (LPS)-induced NF-kappaB activation by inhibiting its nuclear translocation from the cytoplasm. It also inhibited the expression of inducible NO synthase (iNOS) and nitric oxide (NO) production induced by LPS and interferon-gamma. Using enzyme-linked immunosorbent assays (ELISAs) we showed DHMEQ to inhibit LPS-induced secretion of IL-6, IL-12, interleukin-1beta (IL-1beta), and TNF-alpha. Furthermore, DHMEQ also inhibited the phagocytosis of fluorescently labeled Escherichia coli by RAW264.7 cells treated with LPS or IL-1beta, thus being the first evidence for the involvement of NF-kappaB in the regulation of phagocytosis by use of this inhibitor. Deletion of p65 by siRNA also inhibited the phagocytosis. DHMEQ inhibited the LPS-induced but not IL-1beta-induced phagocytosis of glass beads, indicating that activation of not only NF-kappaB but also Toll-like receptor 4 (TLR-4) is essential for the phagocytosis of E. coli. Previously we found that DHMEQ inhibited type 2 collagen-induced rheumatoid arthritis and the growth of various human carcinomas in mice. It is thus likely that inhibition of macrophage activation is involved in the mechanism of these anti-inflammatory and antitumor activities of DHMEQ in mice.

Animals↗
PubMed2006

Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.

Screening of our in-house compound library comprised of intermediates of natural product synthesis projects resulted in discovering two novel gamma-secretase inhibitors, which coincidently had similar moieties, that is, cyclohexenone and two aryl groups arranged on the core six-membered ring. Structure-activity relationship studies of these compounds were also developed.

Amyloid Precursor Protein Secretases↗
PubMed2004

Synthesis of (+)-(2R,3S,4R)-2,3,4-trihydroxycyclohexanone from D-glucose.

We have described the synthesis of (+)-(2R,3S,4R)-2,3,4-trihydroxycyclohexanone by the reduction of a keto-conduritol derivative, the latter being prepared in five steps from (-)-(2S,3R,4S,5S)-2,3,4-tribenzyloxy-5-hydroxycyclohexanone, which is in turn readily synthesized from D-glucose.

Cyclohexanols↗
PubMed2004

Stage-specific surface chemicals of Plodia interpunctella: 2-acyl-1,3-cyclohexanediones from larval mandibular glands serve as cuticular lipids.

Cuticular lipid compositions of all life stages of the stored product moth Plodia interpunctella have been determined. Eggs and adults of P. interpunctella have cuticular lipids consisting solely of hydrocarbons. The composition of eggs and adult females is qualitatively nearly identical with ca. 86 hydrocarbons (11 n-alkanes, 39 monomethyl alkanes, 19 dimethyl alkanes, 11 trimethyl alkanes and 6 monoenes) except females lack the 2-methyl alkanes found in eggs. Adult males have a hydrocarbon composition qualitatively nearly identical to females with the exception that they lack the monoenes. Larval and pupal cuticular lipids are dominated by a mixture of ca. 20 previously described 2-acyl-1,3-cyclohexanediones, with only minute amounts of n-alkanes on the larvae and pupae. The 2-acyl-1,3-cyclohexanediones are continuously secreted onto their silk webbing and food particles by the paired mandibular glands found in all larvae. Extracts from dissected mandibular glands have a qualitatively identical composition to larval cuticular extracts. The pupal stage (which does not have mandibular glands) is enclosed in a silk cocoon also coated with 2-acyl-1,3-cyclohexanediones laid down while the wandering stage larvae spin the cocoon. The 2-acyl-1,3-cyclohexanediones have physical properties which closely mimic those of cuticular hydrocarbons, including melting point and boiling point range and hydrophobicity. This is the first report of an insect with a life stage that does not use conventional cuticular lipids for conservation of water.

Animals↗
PubMed2004

Liquid chromatography-tandem mass spectrometry method for the simultaneous determination of delta-ALA, tyrosine and creatinine in biological fluids.

BACKGROUND: Several acquired and congenital human disorders perturb the concentrations of delta-aminolevulinate (delta-ALA), creatinine and tyrosine in biological fluids. There is currently no facile, sensitive and specific method to measure these analytes simultaneously. METHOD: We developed an LC-MS/MS method to quantify delta-ALA, creatinine and tyrosine in urine that requires minimal sample preparation and no derivatization. The method is also applicable to the analysis of tyrosine in plasma. RESULTS: All calibration plots were linear, with R(2)>or=0.996. Intra- and interday CVs were <10%. The limit of quantitation for delta-ALA was approximately 0.1 micromol/l, and for creatinine and tyrosine it was well below the lowest measured physiological concentrations. The method was applied to analyze urine from 75 healthy volunteers and 43 patients with hereditary tyrosinemia type I (HT I). The mean urinary concentration of delta-ALA in patients (38+/-35 micromol/l, 53+/-30 mg/g creatinine) was higher than that measured in healthy subjects (5.5+/-2.6 micromol/l, 0.9+/-0.2 mg/g creatinine; p<0.001). Treatment with 2-(2-nitro-4-trifluoromethylbenzyl)-1,3-cyclohexanedione (NTBC), an inhibitor of an early step in tyrosine catabolism, decreased urinary delta-ALA (6.4+/-4.8 micromol/l, 13+/-24 mg/g creatinine; p<0.001). The average plasma tyrosine concentration in healthy volunteers (56+/-14 micromol/l) was within normal reference interval used in clinical practice. CONCLUSIONS: The method is simple, specific and precise and allows simultaneous quantitation of delta-ALA, creatinine and tyrosine at concentrations present under physiological or pathophysiological conditions.

Aminolevulinic Acid↗
PubMed2005

Chemistry and biology of moverastins, inhibitors of cancer cell migration, produced by Aspergillus.

Cancer cell migration is a required step in cancer metastasis. We screened for inhibitors of cancer cell migration of microbial origin, and obtained moverastin, a member of the cylindrol family, from Aspergillus sp. F7720. However, the results of an NMR spectroscopic analysis raised the possibility that moverastin is a mixture of two diastereomers. Separation of the C-10 epimers of synthetic moverastin and a bioassay revealed that both diastereomers (moverastins A and B) had inhibitory effects on cell migration. Furthermore, we demonstrated that moverastins A and B inhibited FTase in vitro, and they also inhibited both the membrane localization of H-Ras and the activation of the PI3K/Akt pathway in EC17 cells. Thus, moverastins inhibited the migration of tumor cells by inhibiting the farnesylation of H-Ras, and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.

Alkyl and Aryl Transferases↗
PubMed2006

A small-molecule probe for hepatitis C virus replication that blocks protein folding.

The hepatitis C virus (HCV) is a growing global health problem. Small molecules that interfere with host-viral interactions can serve as powerful tools for elucidating the molecular mechanisms of pathogenesis and defining new strategies for therapeutic development. Using a cell-based screen involving subgenomic HCV replicons, we identified the ability of 18 different abscisic acid (ABA) analogs, originally developed as plant growth regulators, to inhibit HCV replication. Three of these were further studied. One compound, here named origamicin, showed antiviral activity through the inhibition of host proteins involved in protein folding. Origamicin could therefore be an important tool for studying the maturation of both host and viral proteins. Herein we demonstrate an application for molecular scaffolds based on ABA for mammalian cell targets involved in protein folding.

Abscisic Acid↗