Acoplamientos catalizados por paladio en cationes heteroaromáticos: síntesis y propiedades ópticas no lineales de cromóforos catiónicos

Texto en español y resumen en inglésThe development of new organic materials with nonlinear optical properties (NLO) was one of the aims of research over the past decades due to their potential use in the field of telecommunications, optical computing and processing and optical data storage, among others. The advantages of organic compounds compared to inorganic crystals are its low cost, ease of processing and high number of structural variability, which makes them very attractive to industry. Most organic compounds with non-linear optical (NLO) properties are based on highly conjugated molecules with donors and acceptors substituted at the two ends of the molecule, called donor-acceptor (?push-pull?) systems, and these are amongst the most interesting structures for new compounds with efficient NLO responses. The PhD project presented in this report is framed in the context of a search for new molecules push-pull type, based on heteroaromatic cations as acceptors of the system (for these systems has been appointed a new name as "NLO-catiophores), and partly in the development of the synthesis of new macrocyclic rigid cationic nature. First we describe the synthesis and study of nonlinear optical properties by Hyper-Rayleigh Scattering (HRS) of new push-pull system based on heteroaromatic cations. They were obtained through the development of the Suzuki, Heck and Sonogashira reactions. We have demonstrated that organotrifluroborates are better efficient partners than boronic acids for the Suzuki coupling reaction with pyridinium and, Moreover, the ease with which these potassium organotrifluoroborates reacted with azinium and quinolizinium salts in water and the coupling products can be isolated is a further advantage of the procedure and provides a new means for accessing to a great variety of substituted cations. It has proved possible to Heck coupling with aryl iodides with the four isomers of vinilquinolizinium. We have achived the synthesis of a series of D-A and D-A-D catio-phores by Sonogashira cross-coupling reaction from aziniun and quinolizinium bromoderivatives. Noting the overall study ONL values of selected molecules can be obtained the following conclusions: a) heteroaromatic cations type azinium and quinolizinium have good NLO properties (βHRS values between 25-500 10-30 esu). In general, for the pyridinium cation, substitution at the C4 produces best response NLO and in case of cation quinolizinium position C2 is best. b) electrodonating substituent favor the charge transfer on the system Donnor-Acceptor. Moreover it was found that the quinolizinium cation is better acceptor increasing the value of hyperpolarizability. On the other hand, in this context of development of new materials, we considered introducing the quinolizinium system on macrocyclic structures shape-persistent type, i.e. a rigid skeleton formed by aryl units linked together by triple bonds, which resulting in large molecular surfaces. These properties make the AEMs (arylene-ethynylene macrocycles), structures of interest in the field of organic materials

Acoplamientos catalizados por paladio en cationes heteroaromáticos: síntesis y propiedades ópticas no lineales de cromóforos catiónicos

Texto en español y resumen en inglésThe development of new organic materials with nonlinear optical properties (NLO) was one of the aims of research over the past decades due to their potential use in the field of telecommunications, optical computing and processing and optical data storage, among others. The advantages of organic compounds compared to inorganic crystals are its low cost, ease of processing and high number of structural variability, which makes them very attractive to industry. Most organic compounds with non-linear optical (NLO) properties are based on highly conjugated molecules with donors and acceptors substituted at the two ends of the molecule, called donor-acceptor (?push-pull?) systems, and these are amongst the most interesting structures for new compounds with efficient NLO responses. The PhD project presented in this report is framed in the context of a search for new molecules push-pull type, based on heteroaromatic cations as acceptors of the system (for these systems has been appointed a new name as "NLO-catiophores), and partly in the development of the synthesis of new macrocyclic rigid cationic nature. First we describe the synthesis and study of nonlinear optical properties by Hyper-Rayleigh Scattering (HRS) of new push-pull system based on heteroaromatic cations. They were obtained through the development of the Suzuki, Heck and Sonogashira reactions. We have demonstrated that organotrifluroborates are better efficient partners than boronic acids for the Suzuki coupling reaction with pyridinium and, Moreover, the ease with which these potassium organotrifluoroborates reacted with azinium and quinolizinium salts in water and the coupling products can be isolated is a further advantage of the procedure and provides a new means for accessing to a great variety of substituted cations. It has proved possible to Heck coupling with aryl iodides with the four isomers of vinilquinolizinium. We have achived the synthesis of a series of D-A and D-A-D catio-phores by Sonogashira cross-coupling reaction from aziniun and quinolizinium bromoderivatives. Noting the overall study ONL values of selected molecules can be obtained the following conclusions: a) heteroaromatic cations type azinium and quinolizinium have good NLO properties (βHRS values between 25-500 10-30 esu). In general, for the pyridinium cation, substitution at the C4 produces best response NLO and in case of cation quinolizinium position C2 is best. b) electrodonating substituent favor the charge transfer on the system Donnor-Acceptor. Moreover it was found that the quinolizinium cation is better acceptor increasing the value of hyperpolarizability. On the other hand, in this context of development of new materials, we considered introducing the quinolizinium system on macrocyclic structures shape-persistent type, i.e. a rigid skeleton formed by aryl units linked together by triple bonds, which resulting in large molecular surfaces. These properties make the AEMs (arylene-ethynylene macrocycles), structures of interest in the field of organic materials

Efficient functionalization of quinolizinium cations with organotrifluoroborates in water

An efficient functionalization of the quinolizinium system is reported. The reaction of the four isomeric bromoquinolizinium salts with different organotrifluoroborates afforded alkyl-, vinyl-, aryl-, and heteroaryl quinolizinium derivatives in moderate or good yields. Reactions are carried out in water using a counterion exchange for the isolation of the cationic-coupled compounds.Comunidad de Madri

Synthesis of marmycin A and investigation into its cellular activity

Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels-Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel-Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications

Le cuivre contrôle la plasticité cellulaire et déclenche la réponse inflammatoire

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Rapid Access to Ironomycin Derivatives by Click Chemistry

International audienceSalinomycin, a natural carboxylic polyether ionophore, shows a very interesting spectrum of biological activities, including selective toxicity toward cancer stem cells (CSCs). Recently, we have developed a C20-propargylamine derivative of salinomycin (ironomycin) that exhibits more potent activity in vivo and greater selectivity against breast CSCs compared to the parent natural product. Since ironomycin contains a terminal alkyne motif, it stands out as being an ideal candidate for further functionalization. Using copper-catalyzed azide-alkyne cycloaddition (CuAAC), we synthesized a series of 1,2,3-triazole analogs of ironomycin in good overall yields. The in vitro screening of these derivatives against a well-established model of breast CSCs (HMLER CD24low/CD44high) and its corresponding epithelial counterpart (HMLER CD24high/CD44low) revealed four new products characterized by higher potency and improved selectivity toward CSCs compared to the reference compound ironomycin. The present study highlights the therapeutic potential of a new class of semisynthetic salinomycin derivatives for targeting selectively the CSC niche and highlights ironomycin as a promising starting material for the development of new anticancer drug candidates

DMT1 Inhibitors Kill Cancer Stem Cells by Blocking Lysosomal Iron Translocation

International audienceCancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy

Catalytic Semireduction of Internal Alkynes with All-Metal Aromatic Complexes

A simple catalytic method involving all-metal aromatic frameworks as precatalysts ensures an efficient route to (Z)-alkenes. Aromatic triangular palladium clusters were used to reduce internal alkynes without any trace of the formation of alkane side products. These trinuclear complexes provide a catalytic system that parallels the activity and selectivity of their best mononuclear peers, and the catalyst likely operates through complementary mechanism