2. Academic Validation
  3. Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols: A versatile access to restricted isocombretastatin A-4 analogues as antitumor agents

Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols: A versatile access to restricted isocombretastatin A-4 analogues as antitumor agents

  • Eur J Med Chem. 2015 Jan 27:90:834-44. doi: 10.1016/j.ejmech.2014.12.024.
Dolor Renko 1,  Olivier Provot 2,  Evelia Rasolofonjatovo 1,  Jérôme Bignon 3,  Jordi Rodrigo 1,  Joëlle Dubois 3,  Jean-Daniel Brion 1,  Abdallah Hamze 4,  Mouad Alami 5
Affiliations

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 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: olivier.provot@u-psud.fr.
  • 3 Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Dr. J. Bignon, Dr. J. Dubois, avenue de la Terrasse, F-91198 Gif sur Yvette, France.
  • 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: abdallah.hamze@u-psud.fr.
  • 5 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: mouad.alami@u-psud.fr.
PMID: 25528337 DOI: 10.1016/j.ejmech.2014.12.024
Abstract

Potent Anticancer 4-arylchromene agents 6, as restricted isoCA-4 analogues, were prepared with excellent yields by a rapid and versatile synthetic pathway. First, in the presence of PTSA in EtOH, a variety of arylalkynols 9 were transformed into substituted 4-chromanones 10 in a one pot procedure which include regioselective arylalkynols hydration, alcohol etherification, MOM-cleavage, and cyclization. Further palladium coupling reactions, using aryl halides and N-tosylhydrazones 11 gave access to a small library of functionalized 4-arylchromenes 6 with good yields. From this series of 4-arylchromenes, we have identified compound 6s which inhibit tubulin assembly at a micromolar level and demonstrate a remarkable nanomolar level of cytotoxicity against four human Cancer cell lines. Docking studies showed that isoCA-4 and its restricted chromene analogue 6s adopt a similar positioning in the colchicine binding-site of tubulin.

Keywords

4-Arylchromenes; 4-Chromanones; Combretastatin A-4; Cytotoxicity; N-Tosylhydrazones; Tubulin.

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