title: Synthesis, biological evaluation, and structure-activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors.
abstract: The synthesis and structure-activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI(50) = 8-80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC(50) values of 2 and 3 μM, respectively, and induced cell cycle arrest in the G(2)/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity.
authors.affiliation: Université Paris-Sud, CNRS, BioCIS UMR 8076, LabEx LERMIT, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J-B Clément, Châtenay-Malabry, F-92296, France.
authors.forename: Jessy
authors.initials: J
authors.lastname: Aziz
authors.forename: Etienne
authors.initials: E
authors.lastname: Brachet
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamze
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Peyrat
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernadat
authors.forename: Estelle
authors.initials: E
authors.lastname: Morvan
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bignon
authors.forename: Joanna
authors.initials: J
authors.lastname: Wdzieczak-Bakala
authors.forename: Déborah
authors.initials: D
authors.lastname: Desravines
authors.forename: Joelle
authors.initials: J
authors.lastname: Dubois
authors.forename: Marie
authors.initials: M
authors.lastname: Tueni
authors.forename: Ahmad
authors.initials: A
authors.lastname: Yassine
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000475:Alkenes; D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin