Focalisation et structure du texte scénarique

Cet article aborde les processus de focalisation mis en scène dans le texte scénarique. Il s'agit en premier lieu de faire état des différentes modalités de la focalisation dans le texte en établissant la spécificité du cadre scénarique qui relativise le statut des verbes de perception. En second lieu, il s'agit de mettre en évidence la focalisation qu'induisent les relations d'attribution dans le texte scénarique, un personnage étant alors tenu pour responsable d'un flash-arrière. L'article conclut à la nécessité de distinguer les différentes modalités de la focalisation dans le cadre spécifique du texte scénarique.This article studies the différent focalization processes involved in a script. First, the author depicts the modalities of focalization considering the value of the verbs of perception («we see") involved in script's descriptions. In a second time, he examines the focalization introduced by the "relationship of attribution" in a script (the impression of following a character's narration) which introduces a subjective effect in the objective treatment of film narration. In conclusion, he points out the necessity to distinguish différent modalities for the expression of focalization in the script

Cap a la síntesi total de l’anfidinolida E: preparació dels fragments I i II

Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2012, Tutora: Anna Maria Costa ArnauLes anfidinolides són un grup de compostos macrocíclics obtinguts de microorganismes marins amb certes característiques comunes i interessants estructures i activitats biològiques. Per això, la seva síntesi total ha estat àmpliament estudiada per diversos grups de recerca. El present treball està centrat en la síntesi de l'anfidinolida E, en concret en la preparació dels fragments I i II

Visible-Light-Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy

The lack of selectivity of anticancer drugs limits current chemotherapy. Light-activatable drugs, whose activity can be precisely controlled with external light, could provide a more localized action of the drugs in the tumor, thus decreasing side effects and increasing efficacy. Herein, we introduce a series of photoswitchable azobenzene histone deacetylase inhibitors (HDACis) whose activity can be controlled by external visible light. Initial HDACis isomerized under ultraviolet light and were up to >50-fold more active under illumination than in the dark in enzyme assays. These were then optimized toward compounds responding to more permeable and less harmful green light by introducing o-halogen atoms into the azobenzene. Selected compounds decreased cell viability only under illumination in four different cancer cell lines. Overall, we present photoswitchable HDACis with optimized activation wavelengths, which inhibit enzyme activity and cell viability only upon illumination with visible light, contributing to the still limited toolbox of photoswitchable anticancer drugs.L.J.-C. has received funding from the European Union’s Horizon2020 research and innovation programme under Marie Sklodowska-Curie Grant Agreement 841089. A.L. received funding from Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación 10.13039/501100011033 and ERDF A way of making Europe (Projects I+D+i CTQ2017-89222-R and PID2020-120499RB-I00), and the Catalan government (2017 SGR 1604). The authors thank Dr. Lourdes Muñoz from SimChem (IQAC-CSIC) for analytical and instrumental support. The authors thank Dr. Wiktor Szymanski (University of Groningen, Groningen, The Netherlands) for helpful discussions.Peer reviewe

Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect

Photoswitchable molecules exhibit light-dependent biological activity which allow us to control the therapeutic effect of drugs with high precision. Such molecules could solve some of the limitations of anticancer drugs by providing a localised effect in the tumour. Histone deacetylase inhibitors (HDACis) constitute a promising drug class for oncology whose application is often limited by a lack of selectivity. Herein, we developed photoswitchable HDACis based on a hemithioindigo scaffold. We established synthetic routes to access them and determined the optimal conditions for isomerisation and their thermal stability. We then optimised their enzyme activity through three rounds of re-design to identify examples that are up to 6-fold more active under illumination than in the dark. We also confirmed that our best derivative reduces the viability of HeLa cells only under illumination. All in all, we disclose a series of derivatives containing an hemithioindigo moiety, which display a light-dependent effect on both HDAC inhibition and cancer cell viability

Synthetic biomimetic coenzymes and alcohol dehydrogenases for asymmetric catalysis

Redox reactions catalyzed by highly selective nicotinamide-dependent oxidoreductases are rising to prominence in industry. The cost of nicotinamide adenine dinucleotide coenzymes has led to the use of well-established elaborate regeneration systems and more recently alternative synthetic biomimetic cofactors. These biomimetics are highly attractive to use with ketoreductases for asymmetric catalysis. In this work, we show that the commonly studied cofactor analogue 1-benzyl-1,4-dihydronicotinamide (BNAH) can be used with alcohol dehydrogenases (ADHs) under certain conditions. First, we carried out the rhodium-catalyzed recycling of BNAH with horse liver ADH (HLADH), observing enantioenriched product only with unpurified enzyme. Then, a series of cell-free extracts and purified ketoreductases were screened with BNAH. The use of unpurified enzyme led to product formation, whereas upon dialysis or further purification no product was observed. Several other biomimetics were screened with various ADHs and showed no or very low activity, but also no inhibition. BNAH as a hydride source was shown to directly reduce nicotinamide adenine dinucleotide (NAD) to NADH. A formate dehydrogenase could also mediate the reduction of NAD from BNAH. BNAH was established to show no or very low activity with ADHs and could be used as a hydride donor to recycle NADH.BT/Biocatalysi

Identification and preliminary structure-activity relationship studies of 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-ones that induce differentiation of acute myeloid leukemia cells in vitro

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds

Synthetic Biomimetic Coenzymes and Alcohol Dehydrogenases for Asymmetric Catalysis

Redox reactions catalyzed by highly selective nicotinamide-dependent oxidoreductases are rising to prominence in industry. The cost of nicotinamide adenine dinucleotide coenzymes has led to the use of well-established elaborate regeneration systems and more recently alternative synthetic biomimetic cofactors. These biomimetics are highly attractive to use with ketoreductases for asymmetric catalysis. In this work, we show that the commonly studied cofactor analogue 1-benzyl-1,4-dihydronicotinamide (BNAH) can be used with alcohol dehydrogenases (ADHs) under certain conditions. First, we carried out the rhodium-catalyzed recycling of BNAH with horse liver ADH (HLADH), observing enantioenriched product only with unpurified enzyme. Then, a series of cell-free extracts and purified ketoreductases were screened with BNAH. The use of unpurified enzyme led to product formation, whereas upon dialysis or further purification no product was observed. Several other biomimetics were screened with various ADHs and showed no or very low activity, but also no inhibition. BNAH as a hydride source was shown to directly reduce nicotinamide adenine dinucleotide (NAD) to NADH. A formate dehydrogenase could also mediate the reduction of NAD from BNAH. BNAH was established to show no or very low activity with ADHs and could be used as a hydride donor to recycle NADH