title: Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols: A versatile access to restricted isocombretastatin A-4 analogues as antitumor agents.
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.
authors.affiliation: 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.
authors.forename: Dolor
authors.initials: D
authors.lastname: Renko
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Provot
authors.affiliation: 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.
authors.forename: Evelia
authors.initials: E
authors.lastname: Rasolofonjatovo
authors.affiliation: 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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bignon
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodrigo
authors.affiliation: 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.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.affiliation: 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.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.affiliation: 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.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamze
authors.affiliation: 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.
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000438:Alcohols; D000972:Antineoplastic Agents, Phytogenic; D001578:Benzopyrans; D013267:Stilbenes; C058728:fosbretabulin
keywords: 4-Arylchromenes; 4-Chromanones; Combretastatin A-4; Cytotoxicity; N-Tosylhydrazones; Tubulin