title: Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries.
abstract: The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Craven
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Aimon
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Dow
authors.affiliation: Edelris, 115 Avenue Lacassagne, F-69003 Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fleury-Bregeot
authors.affiliation: Edelris, 115 Avenue Lacassagne, F-69003 Lyon, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Guilleux
authors.affiliation: Edelris, 115 Avenue Lacassagne, F-69003 Lyon, France.
authors.forename: Remy
authors.initials: R
authors.lastname: Morgentin
authors.affiliation: Edelris, 115 Avenue Lacassagne, F-69003 Lyon, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Roche
authors.affiliation: Lead Discovery Center GmbH, Otto-Hahn-Straße 15, 44227 Dortmund, Germany.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Kalliokoski
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Foster
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Marsden
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. Electronic address: a.s.nelson@leeds.ac.uk.
authors.forename: Adam
authors.initials: A
authors.lastname: Nelson
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D061565:Cycloaddition Reaction; D015195:Drug Design; D055808:Drug Discovery; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis*
chemical_list: D000470:Alkaloids; D054852:Small Molecule Libraries; D010165:Palladium
keywords: Alkaloid; Aminoarylation; Cycloaddition; Small molecule libraries