title: Natural product-inspired cascade synthesis yields modulators of centrosome integrity.
abstract: In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Dortmund, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Dückert
authors.forename: Verena
authors.initials: V
authors.lastname: Pries
authors.forename: Vivek
authors.initials: V
authors.lastname: Khedkar
authors.forename: Sascha
authors.initials: S
authors.lastname: Menninger
authors.forename: Hanna
authors.initials: H
authors.lastname: Bruss
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Bird
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Maliga
authors.forename: Andreas
authors.initials: A
authors.lastname: Brockmeyer
authors.forename: Petra
authors.initials: P
authors.lastname: Janning
authors.forename: Anthony
authors.initials: A
authors.lastname: Hyman
authors.forename: Stefan
authors.initials: S
authors.lastname: Grimme
authors.forename: Markus
authors.initials: M
authors.lastname: Schürmann
authors.forename: Hans
authors.initials: H
authors.lastname: Preut
authors.forename: Katja
authors.initials: K
authors.lastname: Hübel
authors.forename: Slava
authors.initials: S
authors.lastname: Ziegler
authors.forename: Kamal
authors.initials: K
authors.lastname: Kumar
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis*; D018385:Centrosome / Q000187:drug effects*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D028884:Karyopherins / Q000187:drug effects; D009687:Nuclear Proteins / Q000187:drug effects; D000090243:Nucleophosmin; D011807:Quinolizines / Q000138:chemical synthesis / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D000097606:Exportin 1 Protein
chemical_list: D000470:Alkaloids; D001688:Biological Products; D007211:Indoles; D028884:Karyopherins; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D011807:Quinolizines; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein