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          Institute: MPI für molekulare Zellbiologie und Genetik     Collection: MPI-CBG Publications 2012-arch     Display Documents

ID: 645179.0, MPI für molekulare Zellbiologie und Genetik / MPI-CBG Publications 2012-arch
Natural product-inspired cascade synthesis yields modulators of centrosome integrity.
Authors:Dückert, Heiko; Pries, Verena; Khedkar, Vivek; Menninger, Sascha; Bruss, Hanna; Bird, Alexander W.; Maliga, Zoltan; Brockmeyer, Andreas; Janning, Petra; Hyman, Anthony A.; Grimme, Stefan; Schürmann, Markus; Preut, Hans; Hübel, Katja; Ziegler, Slava; Kumar, Kamal; Waldmann, Herbert
Date of Publication (YYYY-MM-DD):2012
Title of Journal:Nature Chemical Biology
Issue / Number:2
Start Page:179
End Page:184
Copyright:not available
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:nn
Affiliations:MPI für molekulare Zellbiologie und Genetik
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