Studies on Polyethers Produced by Red Algae

Two novel squalene-derived triterpenes, spirodehydrovenustatriol (3) and 14-keto-dehydrothyrsiferol (4) were isolated from the red alga Laurencia viridis, together with two new and unusual C17 terpenoids, adejen A (5) and B (6). These truncated structures possess structural similarities with other known squalene metabolites and their biogenetic origin has been proposed on the basis of an oxidative process of the squalene skeleton. All the structures were elucidated by extensive use of 2D NMR spectroscopic methods

From Broad-Spectrum Biocides to Quorum Sensing Disruptors and Mussel Repellents: Antifouling Profile of Alkyl Triphenylphosphonium Salts

30 páginas, 13 figuras, 4 tablas.-- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited‘Onium’ compounds, including ammonium and phosphonium salts, have been employed as antiseptics and disinfectants. These cationic biocides have been incorporated into multiple materials, principally to avoid bacterial attachment. In this work, we selected 20 alkyl-triphenylphosphonium salts, differing mainly in the length and functionalization of their alkyl chains, in fulfilment of two main objectives: 1) to provide a comprehensive evaluation of the antifouling profile of these molecules with relevant marine fouling organisms; and 2) to shed new light on their potential applications, beyond their classic use as broad-spectrum biocides. In this regard, we demonstrate for the first time that these compounds are also able to act as non-toxic quorum sensing disruptors in two different bacterial models (Chromobacterium violaceum and Vibrio harveyi) as well as repellents in the mussel Mytilus galloprovincialis. In addition, their inhibitory activity on a fouling-relevant enzymatic model (tyrosinase) is characterized. An analysis of the structure-activity relationships of these compounds for antifouling purposes is provided, which may result useful in the design of targeted antifouling solutions with these molecules. Altogether, the findings reported herein provide a different perspective on the biological activities of phosphonium compounds that is particularly focused on, but, as the reader will realize, is not limited to their use as antifouling agentsThis study was supported by the Spanish Ministry of Economy and Competitiveness (http:// www.mineco.gob.es/), SAF2011-28883-C03-01 (JJF), CTQ2011-28417-C02-01/BQU (VSM), AGL2010- 16464 (JMFB), MAT2013-40852-R (FL); Spanish Ministry of Education, Culture and Sport (http://www. mecd.gob.es/portada-mecd/), CEI 10/00018 (MN)Peer reviewe

Identification of 19-epi-okadaic Acid, a New Diarrhetic Shellfish Poisoning Toxin, by Liquid Chromatography with Mass Spectrometry Detection

Okadaic acid (1) (OA) and its congeners are mainly responsible for diarrhetic shellfish poisoning (DSP) syndrome. The presence of several OA derivatives have already been confirmed in Prorocentrum and Dinophysis spp. In this paper, we report on the detection and identification of a new DSP toxin, the OA isomer 19-epi-okadaic acid (2) (19-epi-OA), isolated from cultures of Prorocentrum belizeanum, by determining its retention time (RT) and fragmentation pattern using liquid chromatography coupled with mass spectrometry (LC–MS/MS).Versión del editor3,471

New Polyether Triterpenoids from Laurencia viridis and Their Biological Evaluation

The red seaweed Laurencia viridis is a rich source of secondary metabolites derived from squalene. New polyethers, such as iubol (2), 22-hydroxy-15(28)- dehydrovenustatriol (3), 1,2-dehydropseudodehydrothyrsiferol (4), and secodehydrothyrsiferol (5) have been isolated and characterized from this alga. The structures were determined through the interpretation of NMR spectroscopic data and the relative configuration was proposed on the basis of NOESY spectrum and biogenetic considerations. All new compounds exhibited significant cytotoxic activity against a panel of cancer cell lines

Synthesis and biological evaluation of crown ether acyl derivatives

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Ácido 19-epi-Okadoiko, un nuevo inhibor de PP1 y PP2A

El ácido Okadaico (AO) es un poliéter producido por dinoflagelados del género Prorocentrum y Dinophysis que ha ocasionado un gran impacto en diferentes aspectos como la salud pública, el control de alimentos, la farmacología o la industria pesquera [1]. Este metabolito se aisló inicialmente de una esponja marina [2] y fue caracterizado como el principal agente responsable del síndrome diarreico DSP (diarrethic shellfish poisoning) [3] así como de ser un potente promotor de tumores [4]. Posteriormente se descubrió su mecanismo de acción, el cual implicaba una inhibición selectiva de las proteínas fosfatasas (PPs) [5,6]. Este hecho involucró a estas enzimas a numerosas investigaciones celulares y bioquímicas [7], demostrando el importante papel que tienen estas enzimas en la regulación de distintos procesos celulares como el metabolismo, crecimiento celular o apoptosis, entre otros. Estos resultados han llevado a muchos laboratorios a desarrollar la síntesis completa del AO [8]. En estos momentos en que se están llevando a cabo estudios estructurales con PP1 y PP2A, el descubrimiento de nuevos inhibidores y el estudio de sus conformaciones en disolución es una herramienta muy importante para profundizar en el modo de unión proteína-ligando [9]. En este trabajo, nosotros aportamos el aislamiento, estudio conformacional y actividad farmacológica de un nuevo inhibidor de PP1 y PP2A, el ácido 19- epi-Okadaico (19-epi-AO).Los autores agradecen el apoyo financiero a: MEC (AGL2005- 07294-C04-01); MCYT-FSE (Programa Ramón y Cajal, MLS) y ICIC (PGC). La cepa de P. belizeanum fue cedida por el IEO (Vigo), cortesía de S. Fraga

Ácido Belizeánico, un nuevo derivado del ácido okadaico

En el marco de nuestro programa de búsqueda de nuevas moléculas bioactivas de origen marino, hemos estudiado el dinoflagelado Prorocentrum belizeanum, a partir del cual se encontró el ácido belizeánico. Este es un nuevo derivado del ácido okadaico, del que puede considerarse un precursor de interés. Utilizando fundamentalmente técnicas de resonancia magnética nuclear se determinó su estructura y mediante la utilización de diferentes técnicas de modelización molecular se ha estudiado su conformación en disolución. Es interesante el hecho de que este metabolito también presenta una potente actividad inhibidora de la proteína fosfatasa 2A pese a las diferencias estructurales que presenta con el ácido okadaico

Auto-asociación del ácido okadaico como vía de entrada a las células

[ESP] El ácido okadaico (OA), una toxina de naturaleza polieter producida por dinoflagelados, fue el primer inhibidor natural de proteínas fosfatasas que actúan sobre los residuos de serina y treonina, y que juegan un papel fundamental en la regulación de muchos procesos esenciales en las células. Usando técnicas de “scanning tunneling microscopy (STM)” se puede observar claramente la auto-asociación que sufre dicha toxina, y que parece crucial para su trasporte a través de las membranas celulares [1,2]. Una de las toxinas marinas de distribución mundial, y que causa graves trastornos tanto desde el punto de vista sanitario como socioeconómico, es el ácido okadacio 1 (OA). Sustancia cuyo origen se encuentra en los dinoflagelados de los géneros Dinophysis y Prorocentrum y que produce los síntomas del síndrome diarreico cuando pasa a la cadena trófica a través de marisco contaminado. Estas toxinas cobran una extraordinaria importancia ya que son potentes inhibidores selectivos de las proteínas fosfatasas de tipo 1 y 2A y que las convierte en extraordinarias herramientas farmacológicas para estudiar como se regulan la mayoría de los procesos intracelulares. A pesar de que han sido ampliamente estudiadas desde el punto de vista estructural y biosintético, y que como se ha mencionado, se utilizan a diario como material indispensable en la mayoría de los laboratorios de farmacología, se conoce muy poco de cómo es realmente el mecanismo mediante el cual son capaces de atravesar las membranas biológicas y penetrar en el interior de las células vivas [3]. Hace relativamente poco tiempo en nuestro laboratorio describimos la habilidad que tienen este tipo de sustancias para formar estructuras capaces de albergar un catión metálico, en este caso potasio, y formar dímeros relativamente estables [4,5]. Mediante el uso de STM hemos conseguido establecer cuales son las condiciones propicias para la formación del complejo dimérico con potasio y poderlo observar mediante adsorción sobre monocapas de 111Au (Fig. 1) [6,7]. Utilizando esta tecnología de observación y un modelo sencillo de membrana formado por una bicapa lipídica de fosfatidil colina, hemos conseguido proponer una hipótesis razonable de cómo este tipo de toxinas penetran al interior de la células vivas y ejercen su acción donde la forma dimérica que alberga un catión potasio juega un factor fundamental

Marine Microalgae: Promising Source for New Bioactive Compounds

The study of marine natural products for their bioactive potential has gained strength in recent years. Oceans harbor a vast variety of organisms that offer a biological and chemical diversity with metabolic abilities unrivalled in terrestrial systems, which makes them an attractive target for bioprospecting as an almost untapped resource of biotechnological applications. Among them, there is no doubt that microalgae could become genuine cell factories for the biological synthesis of bioactive substances. Thus, in the course of inter-laboratory collaboration sponsored by the European Union (7th FP) into the MAREX Project focused on the discovery of novel bioactive compounds of marine origin for the European industry, a bioprospecting study on 33 microalgae strains was carried out. The strains were cultured at laboratory scale. Two extracts were prepared for each one (biomass and cell free culture medium) and, thus, screened to provide information on the antimicrobial, the anti-proliferative, and the apoptotic potential of the studied extracts. The outcome of this study provides additional scientific data for the selection of Alexandrium tamarensis WE, Gambierdiscus australes, Prorocentrum arenarium, Prorocentrum hoffmannianum, and Prorocentrum reticulatum (Pr-3) for further investigation and offers support for the continued research of new potential drugs for human therapeutics from cultured microalgae.Peer reviewe

Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

PurposeThe aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA.MethodsAdult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose–response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs.ResultsAdministration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity.ConclusionSubcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity