Lipoxygenase inhibitory tetraketones: potential Remedial source for inflammation and asthma / Las tetracetonas inhibidoras de la lipoxigenasa: fuente potencial Remedial para la inflamación y el asma

OBJETIVE: A series of tetraketones has been synthesized by way of a one pot synthesis and screened for inhibitory activity against the enzyme lipoxygenase. METHOD: An efficient and high yielding one pot synthesis to tetraketones [2-22] has been developed by way of tetraethyl ammonium bromide (Et4N+Br-) mediated condensation of cyclohexane-1, 3-dione [1] with a variety of aldehydes. Lipoxygenase enzyme solution was prepared so that enzyme concentration in reaction mixture was adjusted to give rates of 0.05 absorbance/minute. The test compounds were prepared in methanol of concentrations 50, 25, 12.5, 6.25 and 3.125 µM. The reaction mixture contained 160 µL (100 mM) sodium phosphate buffer (pH 8.0), 10µL of test-compound solution and 20µL of lipoxygenase solution. The contents were mixed and incubated for 10 minutes at 25ºC. The reaction was then initiated by the addition of 10µL substrate solution (linoleic acid, 0.5 mM, 0.12% w/v tween 20 in the ratio of 1:2), with the formation of (9Z,11E)-(13S)-13-hydroperoxyoctadeca-9,11-dienoate, the change of absorbance at 234 nm was followed for 6 minutes. The concentrations of the test compounds that inhibited the lipoxygenase activity by 50% (IC50) were determined by monitoring the effect of increasing concentrations of these compounds in the assays on the degree of inhibition. The IC50 values were calculated by means of the EZ-Fit Enzyme-Kinetics Program (Perrella Scientific Inc., Amherst, USA). RESULT: The tetraketones [2-22] were synthesized in high yields (91-98%) using mild reaction conditions. Most of these compounds showed significant inhibitory activity against the enzyme lipoxygenase. It was found that the presence of substituents which increase delocalization of electrons enhances the inhibitory activity. CONCLUSION: It is concluded that the study is likely to lead to the discovery of therapeutically efficient agents against important disorders such as inflammation and asthma.

OBJETIVO: Una serie de tetracetonas han sido sintetizadas mediante síntesis de varios pasos en un solo reactor (one-pot), y examinadas en relación con su actividad inhibitoria frente a la enzima lipoxigenasa. MÉTODO: Una síntesis one-pot de un rendimiento alto y eficiente para la obtención de tetracetonas (2-22) ha sido desarrollada mediante bromuro amónico tetraetílico (Et4N+Br-) - de ciclohexano-1,3-diona, con una variedad de aldehídos. La solución de enzima lipoxigenasa fue preparada de modo que la concentración de la enzima en las mezcla de la reacción fue ajustada para que diera tasas de 0.05 absorbancia/minuto. Los compuestos de la prueba fueron preparados en metanol de concentraciones (50, 25, 12.5, 6.25 y 3.125 µM). La mezcla de reacción contenía 160 µL (100 mM) de un tampón (buffer) de fosfato de sodio (pH 8.0), 10µL de solución de compuesto de prueba, y 20µL de solución de lipoxigenasa. Los contenidos fueron mezclados e incubados por 10 minutos a 25ºC. La reacción fue iniciada entonces por la adición de 10µL de solución substrato (ácido linoleico, 0.5 mM, 0.12% p/v tween 20 en proporción de 1:2), con la formación de (9Z, 11E)-(13S)-13-hidroperoxioctadeca-9,11-dienoato, el cambio de absorbancia a 234 nm fue seguido por 6 minutos. Las concentraciones de los compuestos de prueba que inhibían la actividad de la lipoxigenasa en un 50% (IC50) fueron determinadas monitoreando el efecto del aumento de las concentraciones de estos compuestos en los ensayos sobre el grado de inhibición. Los valores IC50 fueron calculados mediante el Programa Cinética de la Enzima EZ-Fit (Perrella Scientific Inc., Amherst, USA). RESULTADOS: Las tetracetonas (2-22) se sintetizaron con elevados rendimientos (91-98%) usando condiciones de reacción leve. La mayoría de estos compuestos mostraron una actividad inhibitoria significativa frente a la enzima lipoxigenasa. Se halló que la presencia de sustituyentes que aumentan la deslocalización de los electrones contribuye a mejorar la actividad inhibitoria. CONCLUSIÓN: Se concluye que es probable que el estudio conduzca al descubrimiento de agentes terapéuticamente eficientes frente a trastornos importantes tales como la inflamación y el asma.

Minimum effective release rate of antifoulants. 2. Effects of TBTCI, 2-furyl-n-pentyl ketone and coumaric acid at Snug harbor, Hawaii.

Minimum effective release rate (MERR) of three antifoulants was examined at Snug harbor, Hawaii using a dynamic diffusion system. Among the three antifoulants tested TBTCI was found to be effective in preventing the settlement of Hydroides elegans and Crisea sp at 0.5 microg cm(-2) d(-1) flux rate. At a maximum flux rate of 10 microg cm(-2) d(-1) of 2-furyl-n-pentyl ketone larval settlement of both the test species were 32-36% reduced. More or less similar effect was seen at 10 microg cm(-2) d(-1) of coumaric acid. Non-toxic antifoulants, 2-furyl-n-pentyl ketone and coumaric acid exhibit specific activity against target species. MERR obtainedfor the three antifoulants is discussed.

Effects of piperitenone oxide on the intestinal smooth muscle of the guinea pig

We investigated the effects of piperitenone oxide (PO), a major constituent of the essential oil of Mentha x villosa, on the guinea pig ileum. PO (30 to 740 mug/ml) relaxed basal tonus without significantly alterating the resting membrane potential. In addition, PO relaxed preparations precontracted with either 60 mM K+ or 5 mM tetraethyl-ammonium in a concentration-dependent manner. At concentrations from 0.1 to 10 mug/ml PO potentiated acetylcholine-induced contractions, while higher concentrations (>30 mug/ml) blocked this response. These higher PO concentrations also inhibited contractions induced by 60 mM K+. PO also blocked the components of acetylcholine contraction which are not sensitive to nifedipine or to solutions with nominal zero Ca2+ and EGTA. These results show that PO is a relaxant of intestinal smooth muscle and suggest that this activity may be mediated at least in part by an intracellular effect.