An Unexpected Access to a New Sphingoid Base Containing a Vinyl Sulfide Unit

An unexpected access to a new sphingoid base containing a vinyl sulfide unit is described. The process involves the ‘one-pot' regioselective opening of an epoxide with a thiolate, followed by intramolecular acyl transfer, base-promoted elimination, and final hydrolysis. Excess sodium hydride and high dilution conditions are required for optimal yields. The process is amenable to a variety of thiolates. The resulting compounds can be regarded as new hybrid sphingoid bases that combine some structural motifs present in other reported sphingolipid analogues.Peer reviewe

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline

New aminocyclitols as modulators of glucosylceramide metabolism

7 pages, 3 figures, 4 schemes, 1 table.-- PMID: 15785807 [PubMed].-- Printed version published Mar 2005.A series of 13 aminocyclitol derivatives belonging to two different families is described. Their configuration is governed by the regio- and stereocontrolled epoxide opening of a suitably protected conduritol-B epoxide. Studies on several glycosyl processing enzymes indicate that some of them are good inhibitors of glucosylceramide hydrolase. A rationale to account for preliminary structure–activity relationships is providedFinancial support from Ministerio de Ciencia y Tecnología (Spain), Project BQU2002-03737 and DURSI (Generalitat de Catalunya), Projects 2001SGR00085 and 2001SGR00342 is acknowledged.Peer reviewe

Chemical approaches to sphingolipid research

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/6743

3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells.

Although several reports describe the metabolic fate of sphingoid bases and their analogs, as well as their action and that of their phosphates as regulators of sphingolipid metabolizing-enzymes, similar studies for 3-ketosphinganine (KSa), the product of the first committed step in de novo sphingolipid biosynthesis, have not been reported. In this article we show that 3-ketosphinganine (KSa) and its dideuterated analog at C4 (d2KSa) are metabolized to produce high levels of dihydrosphingolipids in HGC27, T98G and U87MG cancer cells. In contrast, either direct C1 O-phosphorylation or N-acylation of d2KSa to produce dideuterated ketodihydrosphingolipids does not occur. We also show that cells respond to d2KSa treatment with induction of autophagy. Time-course experiments agree with sphinganine, sphinganine 1-phosphate and dihydroceramides being the mediators of autophagy stimulated by d2KSa. Enzyme inhibition studies support that inhibition of Des1 by 3-ketobases is caused by their dihydroceramide metabolites. However, this effect contributes to increasing dihydrosphingolipid levels only at short incubation times, since cells respond to long time exposure to 3-ketobases with Des1 overexpression. The translation of these overall effects into cell fate is discussed.Partial financial support from the ‘‘Ministerio de Ciencia e Innovación’’, Spain (Grants SAF2011-22444), ‘‘Ministerio de Economía y Competitividad’’ (CTQ2014-54743-R), CSIC (Grant PIE 2008801034) and Fundacio´ La Marato´ TV3 (Grant 112130 and 112132) is acknowledged. A PhD fellowship from SENESCYTEcuador to Y. F. O. is also acknowledged. We thank Pedro Rayo for his excellent technical assistance.Peer reviewe

New fluorogenic probes for neutral and alkaline ceramidases

New fluorogenic ceramidase substrates derived from the N-acyl modification of our previously reported probes (RBM14) are reported. While none of the new probes were superior to the known RBM14C12 as acid ceramidase substrates, the corresponding nervonic acid amide (RBM14C24:1) is an efficient and selective substrate for the recombinant human neutral ceramidase, both in cell lysates and in intact cells. A second generation of substrates, incorporating the natural 2-(N-acylamino)-1,3-diol-4-ene framework (compounds RBM15) is also reported. Among them, the corresponding fatty acyl amides with an unsaturated N-acyl chain can be used as substrates to determine alkaline ceramidase (ACER)1 and ACER2 activities. In particular, compound RBM15C18:1 has emerged as the best fluorogenic probe reported so far to measure ACER1 and ACER2 activities in a 96-well plate format. Keywords: ceramides; sphingolipids; substrate; umbelliferone

Stereoselective preparation of quaternary 2-vinyl sphingosines and ceramides and their effect on basal sphingolipid metabolism

The dicyclohexylborane-mediated addition of allene 1 to (E)-2-tridecenal affords a quaternary protected 2-amino-2-vinyl-1,3-diol in good yield as a single diastereomer. This compound is readily transformed into the four stereoisomers of the quaternary (E)-2-vinyl analogs of sphingosine. The metabolic fate and the effect of these compounds on the basal sphingolipid metabolism in human A549 lung adenocarcinoma cells has been studied, together with the ceramide analog of the most relevant vinylsphingosine derivative

Paisagem

Neste número temático da revista Estúdio lançou-se o desafio aos criadores e artistas para debaterem e estudarem a obra de seus companheiros de profissão, outros artistas, dentro do tema da paisagem.Poderemos, a posteriori, agrupar os 39 artigos, aqui aprovados e apresentados, segundo quatro eixos temáticos: a. Testemunho da paisagem; b. Perda da paisagem; c. Paisagens urbanas; d. Sustentabilidade. No primeiro núcleo, testemunho da paisagem, consideramos os artigos que refletem sobre artistas cuja obra integra uma componente contemplativa, onde se sente a busca de um sentido profundo. No segundo núcleo, perda da paisagem, poderemos agrupar os artigos que se debruçam sobre formas de resgate de algo que se sente estar perdido. Reflete-se sobre os vestígios de um mundo antigo, sem quebras, sem separações entre o homem e a natureza, ou sobre a nostalgia da sua recuperação através de uma redenção introspetiva. No terceiro núcleo, paisagens urbanas, encontramos artigos que meditam sobre a textura ambiental urbana e sobre os meios de simulação inerentes aos recursos cenográficos presentes nos espaços públicos e partilhados por um elo social: os espaços codificados. No quarto núcleo acompanhamos a tendência mais ou menos ativista, onde o artista carrega o peso do perigo, a ameaça sobre os sistemas vivos, e receia o fim das paisagens. A sustentabilidade exige agilidade e alterações nos estilos de vida, exige uma economia reinventada. Agruparam-se assim os artigos seguindo uma teia de afinidades, sendo decerto uma organização segundo critérios de oportunidade temática: encontrar texturas globais no tecido do discurso sobre arte, nos textos dos artistasinfo:eu-repo/semantics/publishedVersio

Nuevos análogos conformacionalmente restringidos de la metoxamina

[spa] Las modificaciones moleculares que constituyen el objetivo de la presente Tesis pretenden aportar nuevos datos que permitan un más amplio conocimiento de los requisitos estructurales y estereoquímicos necesarios tanto para la actividad como para la selectividad adrenérgica, lo que puede conducir a una mejor comprensión de las interacciones fármaco-receptor. Todo ello sólo habrá de ser posible si se parte de un modelo flexible adecuado y, a nuestro entender, la metoxamina lo es especialmente dadas sus propiedades farmacológicas. Se trata de un fármaco polivalente, lo que permite el estudio simultáneo de los receptores adrenérgicos alfa y beta; además, carece de efectos adrenérgicos indirectos que vendrían a complicar el resultado de la valoración farmacológica. Finalmente, un aspecto no desdeñable es la asequibilidad de gran parte de los productos de partida necesarios y la posibilidad de extender a nuestro caso varias de las vías sintéticas mejor establecidas para la obtención de aminoalcoholes vecinales de estereoquímica definida. La presente Memoria se ha dividido en cuatro apartados generales, de los que los tres primeros corresponden a la descripción de los procesos de síntesis conducentes a cada uno de los tipos de análogos cíclicos que constituyen nuestro objetivo. El último Capítulo se dedica a la discusión de los resultados farmacológicos obtenidos y al establecimiento de las relaciones estereoquímica-actividad