Synthesis and antiproliferative activity of novobiocin analogues as potential hsp90 inhibitors

  • Eur J Med Chem. 2014 Aug 18:83:498-507. doi: 10.1016/j.ejmech.2014.06.067.
Davide Audisio  1 ,  Délphine Methy-Gonnot  2 ,  Christine Radanyi  2 ,  Jack-Michel Renoir  2 ,  Stéphanie Denis  2 ,  Félix Sauvage  2 ,  Juliette Vergnaud-Gauduchon  2 ,  Jean-Daniel Brion  1 ,  Samir Messaoudi  3 ,  Mouad Alami  4
Affiliations
  • 1. University Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Equipe Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry F-92296, France.
  • 2. Institut Galien-Paris Sud, CNRS, UMR 8612, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry F-92296, France.
  • 3. University Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Equipe Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry F-92296, France. Electronic address: [email protected].
  • 4. University Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Equipe Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry F-92296, France. Electronic address: [email protected].
PMID: 24992077 DOI: 10.1016/j.ejmech.2014.06.067
Abstract

A series of substituted coumarins1-10 was designed and synthesized as a novel class of 4TCNA analogues. Compound 2a showed excellent antiproliferative activity with mean GI50 values at a micromolar level in a diverse set of human Cancer cells (GI50 = 2-30 μM) and induced a high Apoptosis level in MCF-7 breast Cancer cell line. The molecular signature of HSP90 inhibition was assessed by depletion of the Erα HSP90 client protein.

Keywords
4TCNA; 6BrCaQ; Apoptosis; Cytotoxicity; Hsp90.