RESUMEN
The European Federation for Medicinal chemistry and Chemical biology (EFMC) is a federation of learned societies. It groups organizations of European scientists working in a dynamic field spanning chemical biology and medicinal chemistry. New ideas, tools, and technologies emerging from a wide array of scientific disciplines continuously energize this rapidly evolving area. Medicinal chemistry is the design, synthesis, and optimization of biologically active molecules aimed at discovering new drug candidates - a mission that in many ways overlaps with the scope of chemical biology. Chemical biology is by now a mature field of science for which a more precise definition of what it encompasses, in the frame of EFMC, is timely. This article discusses chemical biology as currently understood by EFMC, including all activities dealing with the design and synthesis of biologically active chemical tools and their use to probe, characterize, or influence biological systems.
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Preparaciones Farmacéuticas/química , Química Farmacéutica , Europa (Continente) , Humanos , Preparaciones Farmacéuticas/síntesis químicaRESUMEN
Proline-based trypsin inhibitors occupying the S1-S2-S1' region were identified by an HTS screening campaign. It was discovered that truncation of the P1' moiety and appropriate extension into the S4 region led to highly potent trypsin inhibitors with excellent selectivity against related serine proteases and a favorable hERG profile.
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Pancreatitis/tratamiento farmacológico , Inhibidores de Tripsina/síntesis química , Inhibidores de Tripsina/uso terapéutico , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Tripsina/química , Inhibidores de Tripsina/farmacologíaRESUMEN
Chemogenetic libraries, collections of well-defined chemical probes, provide tremendous value to biomedical research but require substantial effort to ensure diversity as well as quality of the contents. We have assembled a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our approach, lessons learned, and disclosing our current collection of 4,185 compounds with their primary annotated gene targets (https://github.com/Novartis/MoaBox). This physical collection is regularly updated and used broadly both within Novartis and in collaboration with external partners.
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Sondas Moleculares/química , Bibliotecas de Moléculas Pequeñas/química , Bioensayo , Bases de Datos de Compuestos Químicos , Descubrimiento de Drogas , Humanos , Aprendizaje Automático , Sondas Moleculares/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismoRESUMEN
An efficient synthesis of the macrocyclic core of (-)-pladienolide B is disclosed. The concise route relies on a chiral auxiliary-mediated asymmetric aldol addition and an osmium-catalyzed asymmetric dihydroxylation to install the three oxygenated stereocenters of the macrocycle. This purely reagent-controlled and flexible strategy sets the stage for future analogue syntheses and structure-activity relationship plotting of the appealing anticancer lead structure pladienolide B.
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Compuestos Epoxi/síntesis química , Macrólidos/síntesis química , Alquenos/síntesis química , Alquenos/química , Cristalografía por Rayos X , Compuestos Epoxi/química , Compuestos Epoxi/metabolismo , Macrólidos/química , Macrólidos/metabolismo , Modelos Moleculares , Estructura Molecular , Streptomyces/química , Streptomyces/metabolismoRESUMEN
An efficient synthesis of the macrocyclic core of laulimalide with a pendant vinyl group at C20 is described, allowing for late-stage introduction of various side chains through a selective and efficient cross metathesis diversification step. Representative analogues reported herein are the first to contain modifications to only the side chain dihydropyran of laulimalide and des-epoxy laulimalide. This step-economical strategy enables the rapid synthesis of new analogues using alkenes as an inexpensive, abundantly available diversification feedstock.
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Compuestos Macrocíclicos/síntesis química , Taxoides/química , Macrólidos , Estructura MolecularRESUMEN
An efficient strategy is described for the synthesis of enantiopure calystegine alkaloids. The key step employs a zinc-mediated fragmentation of benzyl-protected methyl 6-iodo-glycosides followed by in situ formation of the benzyl imine and Barbier-type allylation with zinc, magnesium, or indium metal. Stereochemistry in the pivotal allylation is controlled by the choice of the metal. The functionalized 1,8-nonadienes, thus formed, are converted into cycloheptenes by ring-closing olefin metathesis. Regioselective hydroboration and oxidation give the corresponding cycloheptanones, which are deprotected to afford the desired calystegines. Hereby, calystegine B(2), B(3), and B(4) are prepared from D-glucose, D-galactose, and D-mannose, respectively. This route constitutes the shortest synthesis of calystegine B(2) and gives rise to the first total syntheses of calystegine B(3) and B(4).