Acide | EPFL Graph Search

Un acide est un composé chimique minéral ou organique accepteur, au sens large, de doublets électroniques. Il est généralement défini par des réactions-types dans différents solvants, en particulier en libérant l'ion hydronium dans l'eau. Les acides réagissent souvent en dégageant de l'énergie avec d'autres composés chimiques appelés bases (les alcalis des Anciens), qui, elles, donnent des doublets électroniques et ont le pouvoir de générer, en tout ou partie, l'ion hydroxyle dans l'eau. Les acides forts, dans un milieu solvant donné, initient des réactions complètes et rapides, transformant le solvant en sa forme la plus acide ; les acides faibles contribuent à des réactions équilibrées. L'existence de plusieurs fonctionnalités acides au sein d'un même composé chimique caractérise les polyacides. Dans le cadre de la théorie de Brønsted-Lewis, le pH d'une solution obtenue en dissolvant un acide dans l'eau est inférieur à sept. Les acides sont connus depuis l'Antiquité pour leur po

Peptide-Polymer Conjugates for Therapeutic Applications

Ana Maria Raduta

Over the last ten years the attention of the pharmaceutical industry has shifted away from small molecules to focus on new biologics such as antibodies, proteins and therapeutic peptides. Herein, peptides have emerged as a particularly interesting category that fills a niche between small molecule chemicals and the larger proteins. Although they have great potential for drug development, their use is still limited due to their intrinsic low systemic stability, rapid renal elimination and poor membrane permeability. Various formulations have been developed to take advantage of their therapeutic properties, one of the most promising strategies being chemical conjugation to a polymer. Peptide-polymer conjugates are hybrid materials that consist of one or more synthetic polymers covalently attached to one or more peptide fragments. The aim of this thesis was to provide an insight into the requirements for the design of peptide-polymer conjugates for therapy. Chapter 1 illustrates the state of the art in the development of peptides for therapeutic applications, exemplifies the different architectures and structures of peptide-polymer conjugates and discusses ongoing efforts to improve and diversify the range and applications of these conjugates. Chapter 2 describes a novel synthetic strategy to prepare PHPMA based peptide-polymer conjugates via thiol chemistry starting from poly(pentafluorophenyl methacrylate). By varying the feed composition, the extent of side chain modification could be controlled. Further modification of the reactive copolymer scaffolds led to the site specific attachment of model peptides. This method was used to synthesize stable as well as pH and redox sensitive peptide-polymer conjugates and the release of the peptide from the polymer backbone was studied in acidic and redox conditions. In Chapter 3, the aim was to construct a peptide-polymer conjugate that could serve to promote intracellular delivery and drug release but also play a role in the intracellular trafficking of the drug. To this end, coiled coil peptides E3/K3 was attached to a PHPMA polymer backbone and was used to facilitate release from the backbone at acidic pH and further endosomal escape. Initially, the membrane lytic properties of E3/K3 and three newly designed E3/K3X motifs on model membranes were investigated as a function of pH. Secondly, the potential application of E3/K3 peptide-polymer conjugate for cytoplasmic delivery was evaluated in vitro. Chapter 4 explores the synthesis and in vitro therapeutic activity of synthetic peptide-polymer conjugates focusing on the inhibition of an oncogenic transcription factor (AP-1). To this end, AFosW peptide, a peptide binder that can interfere with AP-1 formation was attached to a polymer backbone via a redox or pH sensitive linker using a strategy developed in Chapter 2. Fluorescent microscopy and flow cytometry provided an insight into the cellular uptake of these conjugates. Their ability to interfere with AP-1 formation in vitro was quantified. Chapter 5 describes the synthesis of a second generation of peptide-polymer conjugates for AP-1 inhibition that along the FosW dominant negative peptide also incorporates a motif that facilitates endosomal escape and a nuclear localization sequence. To investigate the potential application for therapy, the conjugates were evaluated and compared with regard to their ability to inhibit AP-1 formation in living cells.

EPFL2015

Acid-base-induced fac → mer isomerization of luminescent iridium(iii) complexes

Farzaneh Fadaei Tirani, Anastasia Gitlina, Carolina Luciana Plaice, Albert Ruggi, Kay Severin

Luminescent Ir(C^N)3 complexes (C^N = cyclometalated arylpyridine ligand) exist in the form of two stable isomers with distinct photophysical and electrochemical properties: fac and mer. Herein, we show that fac-Ir(C^N)3 complexes can be converted into the thermodynamically less stable mer forms by a consecutive reaction with first acid and then base. The chemically induced isomerization is fast, quantitative, and stereoselective, and it can be inversed by light. The new isomerization process opens the possibility to use highly luminescent Ir(C^N)3 complexes as molecular switches.

2022

The dilemma between acid and base catalysis in the synthesis of benzimidazole from o-phenylenediamine and carbon dioxide

Alexy Robert Bonnin, Paul Joseph Dyson, Martin Hulla, Simon Nussbaum

The tandem synthesis of benzimidazole and other azoles can be achived by the N-formylation of ortho-substituted anilines followed by a cyclization reaction. However, CO2-based N-formylations with hydrosilane reducing agents are base catalyzed whereas the cyclization reaction is acid catalyzed. The mismatch in catalytic conditions means that only one of the steps can be catalyzed in a single pot reaction. While the N-formylation reaction is frequently the target of catalyst development, the cyclization reaction requires comparably much harsher reaction conditions. Identification of these difficulties lead us to the development of a one-pot, two-step synthesis of benzimidazole under mild reaction conditions employing acid catalysts.

2019

Peptide-Polymer Conjugates for Therapeutic Applications

Ana Maria Raduta

EPFL2015