title: Positional Scanning Synthesis of a Peptoid Library Yields New Inducers of Apoptosis that Target Karyopherins and Tubulin.
abstract: We describe the synthesis of a library of 11, 638 N-alkylglycine peptoid trimers in a positional scanning format with adjustment of reaction conditions to account for different reactivities of the monomer building blocks. Evaluation of the library by high-content phenotypic screening for modulators of the cytoskeleton and mitosis resulted in the identification of two apoptosis-inducing peptoids, which, despite their structural similarity, target different proteins and cellular mechanisms. Whereas one peptoid binds to karyopherins, which mediate nuclear transport, the other N-alkylglycine trimer binds tubulin at the vinca alkaloid binding site.
authors.affiliation: Department of Chemical Biology, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany).|Department of Biological Chemistry and Molecular Modeling, Institut de Química Avançada de Catalunya (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona (Spain).
authors.forename: Glòria
authors.initials: G
authors.lastname: Vendrell-Navarro
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institut de Química Avançada de Catalunya (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona (Spain).
authors.forename: Federico
authors.initials: F
authors.lastname: Rúa
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institut de Química Avançada de Catalunya (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona (Spain).
authors.forename: Jordi
authors.initials: J
authors.lastname: Bujons
authors.affiliation: Department of Chemical Biology, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany).
authors.forename: Andreas
authors.initials: A
authors.lastname: Brockmeyer
authors.affiliation: Department of Chemical Biology, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany).
authors.forename: Petra
authors.initials: P
authors.lastname: Janning
authors.affiliation: Department of Chemical Biology, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany).
authors.forename: Slava
authors.initials: S
authors.lastname: Ziegler
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institut de Química Avançada de Catalunya (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona (Spain).
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.affiliation: Department of Chemical Biology, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany). herbert.waldmann@mpi-dortmund.mpg.de.|Lehrbereich Chemische Biologie, Fakultät Chemie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany). herbert.waldmann@mpi-dortmund.mpg.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D019151:Peptide Library; D034444:Peptoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D028884:Karyopherins; D019151:Peptide Library; D034444:Peptoids; D014404:Tubulin
keywords: apoptosis; combinatorial chemistry; peptidomimetics; peptoids; structure-activity relationships