title: IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity.
abstract: A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N-toluenesulfonylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatin A-4 (isoCA-4) analogues that lack the 3,4,5-trimethoxyphenyl ring, displayed nanomolar-level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)phenol (4 b), 4-[1-(3-fluoro-4-methoxyphenyl)vinyl]-2-methylquinazoline (4 c), and 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)aniline (4 d), which respectively bear the greatest resemblance to isoCA-4, isoFCA-4, and isoNH2 CA-4, are able to arrest HCT116 cancer cells in the G2 /M cell-cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.
authors.affiliation: Univ. 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, 92296 (France).
authors.forename: Mohamed Ali
authors.initials: MA
authors.lastname: Soussi
authors.affiliation: Univ. 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, 92296 (France). olivier.provot@u-psud.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Provot
authors.affiliation: Univ. 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, 92296 (France).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bernadat
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette (France).
authors.forename: Jérome
authors.initials: J
authors.lastname: Bignon
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette (France).
authors.forename: Déborah
authors.initials: D
authors.lastname: Desravines
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette (France).
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.affiliation: Univ. 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, 92296 (France).
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Brion
authors.affiliation: Univ. 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, 92296 (France). samir.messaoudi@u-psud.fr.
authors.forename: Samir
authors.initials: S
authors.lastname: Messaoudi
authors.affiliation: Univ. 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, 92296 (France). mouad.alami@u-psud.fr.
authors.forename: Mouad
authors.initials: M
authors.lastname: Alami
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001632:Bibenzyls / Q000737:chemistry*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity
chemical_list: D001632:Bibenzyls; D011799:Quinazolines; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin
keywords: cancer; combretastatins; cytotoxicity; isoCA-4; quinazolines; tubulin