RESUMO
Hydrodistilled oil from leaves of the Ethiopian plant Laggera tomentosa has been shown to contain (-)-chrysanthenone (5%), (-)/(+)-filifolone (92:8; 8%) and (Z)-isogeranic acid (8%)-all likely to be artefacts. The main constituent of the oil, (+)-chrysanthenone (53%), is believed to be the precursor undergoing thermal and solvolytic reactions during the hydrodistillation process.
Assuntos
Boranos , Óleos Voláteis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Asteraceae/química , Cromatografia Gasosa , Extratos Vegetais/análiseRESUMO
In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.
Assuntos
Inibidores de Ciclo-Oxigenase/isolamento & purificação , Inibidores de Ciclo-Oxigenase/farmacologia , Ácidos Graxos/farmacologia , Isoenzimas/metabolismo , Plantago/química , Plantas Medicinais , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Bovinos , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/síntese química , Ácidos Graxos/química , Metilação , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Microssomos/metabolismo , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/isolamento & purificação , OvinosRESUMO
Three 1,3-dithiolanes and four 1,3-dithianes have been synthesised from 1-(1,3-dithiolan-2-yl)-2-propanone and 1-(1,3-dithian-2-yl)-2-propanone, respectively. Asymmetric reductions of these ketones using baker's yeast gave the corresponding enantiopure (S)-alcohols. Baker's yeast also reduced the double bond in 3-(1,3-dithian-2-yl)-3-buten-2-one enantioselectively to give (S)-3-(1,3-dithian-2-yl)-2-butanone. 3-(1,3-Dithian-2-yl)-3-buten-2-one was also reduced chemo-selectively and the resulting 3-(1,3-dithian-2-yl)-3-buten-2-ol was resolved by transesterification in organic solvent using lipase B from Candida antarctica to yield the (S)-alcohol and the (R)-acetate with very high enantiomeric ratio, E. Racemic 1-(1,3-dithiolan-2-yl)-2-propanol and 1-(1,3-dithian-2-yl)-2-propanol were also resolved under similar conditions to give the (S)-alcohols and the corresponding (R)-acetates.
Assuntos
Compostos Heterocíclicos com 1 Anel/síntese química , Lipase/metabolismo , Saccharomyces cerevisiae/química , Enzimas Imobilizadas , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/isolamento & purificação , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Oxirredução , Saccharomyces cerevisiae/enzimologia , Estereoisomerismo , Compostos de Enxofre/síntese química , Compostos de Enxofre/química , Compostos de Enxofre/farmacologiaRESUMO
With the aim of enhancing selectively the beneficial biological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) a number of polyunsaturated fatty acids containing sulfur or oxygen atoms in the chain has been synthesized starting from EPA and DHA, respectively. Oxidative degradation of these acids led to the corresponding aldehydes all-(Z)-3,6,9,12-pentadecatetraenal and all-(Z)-3,6,9,12,15-octadecapentaenal. Reactions with DBU converted these aldehydes quantitatively into the conjugated isomers (2E,6Z,9Z,12Z)-pentadecatetraenal and (2E,6Z,9Z,12Z,15Z)-octadecapentaenal, respectively. The four aldehydes were transformed by a sequence of reactions comprising reduction to the alcohols, halogenation and substitution with mercapto esters into the corresponding sulfur containing polyunsaturated fatty acid esters. The oxygen containing esters were prepared from the respective alcohol by boron trifluoride catalysed reaction with ethyl diazoacetate.
Assuntos
Ácidos Docosa-Hexaenoicos/síntese química , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/síntese química , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/química , Hidrólise , Espectroscopia de Ressonância MagnéticaRESUMO
TNF signaling mechanisms involved in activation of transcription factor NF-kappaB were studied in the human keratinocyte cell line HaCaT. We show that TNF-induced activation of NF-kappaB was inhibited by the well-known selective inhibitors of cytosolic phospholipase A2 (cPLA2): the trifluoromethyl ketone analogue of arachidonic acid (AACOCF3) and methyl arachidonyl fluorophosphate. The trifluoromethyl ketone analogue of eicosapentaenoic acid (EPACOCF3) also suppressed TNF-induced NF-kappaB activation and inhibited in vitro cPLA2 enzyme activity with a similar potency as AACOCF3. The arachidonyl methyl ketone analogue (AACOCH3) and the eicosapentanoyl analogue (EPACHOHCF3), which both failed to inhibit cPLA2 enzyme activity in vitro, had no effect on TNF-induced NF-kappaB activation. TNF-induced NF-kappaB activation was also strongly reduced in cells stimulated in the presence of the secretory PLA2 (sPLA2) inhibitors 12-epi-scalaradial and LY311727. Addition of excess arachidonic acid suppressed the inhibitory effect of 12-epi-scalaradial and LY311727. Moreover, both methyl arachidonyl fluorophosphate and 12-epi-scalaradial blocked TNF-mediated enhancement of expression of ICAM-1. Activation of NF-kappaB by IL-1beta was markedly less sensitive to both cPLA2 and sPLA2 inhibitors. The results indicate that both cPLA2 and sPLA2 may be involved in the TNF signal transduction pathway leading to nuclear translocation of NF-kappaB and to NF-kappaB-activated gene expression in HaCaT cells.
Assuntos
Citosol/enzimologia , Inibidores Enzimáticos/farmacologia , Molécula 1 de Adesão Intercelular/biossíntese , NF-kappa B/antagonistas & inibidores , Fosfolipases A/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Ácido Araquidônico/antagonistas & inibidores , Ácido Araquidônico/metabolismo , Ácidos Araquidônicos/farmacologia , Linhagem Celular , Citosol/efeitos dos fármacos , Citosol/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacologia , Vetores Genéticos , Homosteroides/farmacologia , Humanos , Insetos/genética , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Interleucina-1/antagonistas & inibidores , Interleucina-1/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Organofosfonatos/farmacologia , Fosfolipases A/genética , Fosfolipases A/metabolismo , Fosfolipases A2 , Proteínas Recombinantes/antagonistas & inibidores , Sesterterpenos , Terpenos/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Alpha-ethyl-, alpha-methyl- and beta-methyl eicosapentaenoic acid (EPA) were prepared and their incorporation into cell lipids and effects on eicosanoid synthesis compared with EPA and docosahexaenoic acid (DHA). alpha- and beta-methyl EPA were incorporated into hepatocyte triacylglycerols as efficiently as EPA, whereas lesser amounts were found in phospholipids. alpha-ethyl EPA was not incorporated into phospholipids but small amounts were detected in triacylglycerol. All derivatives inhibited the synthesis of arachidonic acid, although less efficiently than EPA and DHA. The derivatives were poor substrates of prostaglandin H (PGH) synthase and 5-lipoxygenase, and they all inactivated PGH synthase. In isolated platelets, alpha-methyl EPA was a stronger inhibitor of TxB2 production than EPA, alpha-ethyl- and beta-methyl EPA. All derivatives were stronger inducers of peroxisomal beta-oxidation than EPA and DHA. This increased induction probably is a consequence of the blocked mitochondrial beta-oxidation of the derivatives.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacologia , Fosfolipídeos/biossíntese , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Ácido Araquidônico/biossíntese , Linhagem Celular , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Cinética , Ácido Linoleico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ratos , Relação Estrutura-Atividade , Tromboxano B2/biossíntese , Triglicerídeos/biossínteseRESUMO
This study reports the effects of a novel polyunsaturated 3-thia fatty acid, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on serum lipids and key enzymes in hepatic fatty acid metabolism compared to a saturated 3-thia fatty acid, tetradecylthioacetic acid. Palmitic acid treated rats served as controls. Fatty acids were administered by gavage in daily doses of 150 mg/kg body weight for 10 days. The aim of the present study was: (a) To investigate the effect of a polyunsaturated 3-thia fatty acid ester, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on plasma lipids in normolipidemic rats: (b) to verify whether the lipid-lowering effect could be consistent with enhanced fatty acid oxidation: and (c) to study whether decreased activity of esterifying enzymes and diversion to phospholipid synthesis is a concerted mechanism in limiting the availability of free fatty acid as a substrate for hepatic triglyceride formation. Repeated administration of the polyunsaturated 3-thia fatty acid ester for 10 days resulted in a reduction of plasma triglycerides (40%), cholesterol (33%) and phospholipids (20%) compared to controls. Administration of polyunsaturated and saturated 3-thia fatty acids (daily doses of 150 mg/kg body weight) reduced levels of lipids to a similar extent and followed about the same time-course. Both mitochondrial and peroxisomal fatty acid oxidation increased (1.4-fold- and 4.2-fold, respectively) and significantly increased activities of carnitine palmitoyltransferase (CPT) (1.6-fold), 2,4-dienoyl-CoA reductase (1.2-fold) and fatty acyl-CoA oxidase (3.0-fold) were observed in polyunsaturated 3-thia fatty acid treated animals. This was accompanied by increased CPT-II mRNA (1.7-fold). 2,4-dienoyl-CoA reductase mRNA (2.9-fold) and fatty acyl-CoA oxidase mRNA (1.7-fold). Compared to controls, the hepatic triglyceride biosynthesis was retarded as indicated by a decrease in liver triglyceride content (40%). The activities of glycerophosphate acyltransferase, acyl-CoA: 1,2-diacylglycerol acyltransferase and CTP:phosphocholine cytidylyltransferase were increased. The cholesterol lowering effect was accompanied by a reduction in HMG-CoA reductase activity (80%) and acyl-CoA:cholesterol acyltransferase activity (33%). In hepatocytes treated with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate, fatty acid oxidation was increased 1.8-fold compared to controls. The results suggest that treatment with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate reduces plasma triglycerides by a decrease in the availability of fatty acid substrate for triglyceride biosynthesis via enhanced fatty acid oxidation, most likely attributed to the mitochondrial fatty acid oxidation. It is hypothesized that decreased phosphatidate phosphohydrolase activity may be an additive mechanism which contribute whereby 3-thia fatty acids reduce triglyceride formation in the liver. The cholesterol-lowering effect of the polyunsaturated 3-thia fatty acid ester may be due to changes in cholesterol/cholesterol ester synthesis as 60% of this acid was observed in the hepatic cholesterol ester fraction.