Natural product-inspired cascade synthesis yields modulators of centrosome integrity

Nat Chem Biol. 2011 Dec 25;8(2):179-84. doi: 10.1038/nchembio.758.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis
  • Alkaloids / pharmacology
  • Biological Products / chemical synthesis*
  • Centrosome / drug effects*
  • Exportin 1 Protein
  • Indoles / chemical synthesis
  • Indoles / pharmacology
  • Karyopherins / drug effects
  • Nuclear Proteins / drug effects
  • Nucleophosmin
  • Quinolizines / chemical synthesis
  • Quinolizines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / drug effects

Substances

  • Alkaloids
  • Biological Products
  • Indoles
  • Karyopherins
  • Nuclear Proteins
  • Quinolizines
  • Receptors, Cytoplasmic and Nuclear
  • Nucleophosmin

Associated data

  • PubChem-Substance/131287889
  • PubChem-Substance/131287890
  • PubChem-Substance/131287891
  • PubChem-Substance/131287892
  • PubChem-Substance/131287893
  • PubChem-Substance/131287894
  • PubChem-Substance/131287895
  • PubChem-Substance/131287896
  • PubChem-Substance/131287897
  • PubChem-Substance/131287898
  • PubChem-Substance/131287899
  • PubChem-Substance/131287900
  • PubChem-Substance/131287901
  • PubChem-Substance/131287902
  • PubChem-Substance/131287903
  • PubChem-Substance/131287904
  • PubChem-Substance/131287905
  • PubChem-Substance/131287906
  • PubChem-Substance/131287907
  • PubChem-Substance/131287908
  • PubChem-Substance/131287909
  • PubChem-Substance/131287910
  • PubChem-Substance/131287911
  • PubChem-Substance/131287912
  • PubChem-Substance/131287913
  • PubChem-Substance/131287914
  • PubChem-Substance/131287915
  • PubChem-Substance/131287916
  • PubChem-Substance/131287917
  • PubChem-Substance/131287918
  • PubChem-Substance/131287919