title: Discovery of azaisoerianin derivatives as potential antitumors agents.
abstract: A series of N-methyl-diarylamines 2 was designed and synthesized as a novel class of CA-4 and isoCA-4 analogues. Compounds 2b and 2m showed excellent antiproliferative activity with mean GI50 values at a nanomolar level in a diverse set of human cancer cells. These compounds also inhibited tubulin assembly at a micromolar range, arrested the cellular cycle in the G2/M phase and induced apoptosis at very low concentrations. Preliminary in vitro results revealed that 2b and 2m displayed substantial efficacy as potent antivascular agents. Docking studies indicates that these lead compounds showed a binding mode similar to those observed with isoCA-4 at the colchicine binding site of tubulin.
authors.affiliation: Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, LabEx LERMIT, Equipe Labellisée Ligue Contre le Cancer, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-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, LabEx LERMIT, Equipe Labellisée Ligue Contre le Cancer, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-92296, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Provot
authors.affiliation: Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, LabEx LERMIT, Equipe Labellisée Ligue Contre le Cancer, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-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, Gif sur Yvette F-91198, 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, Gif sur Yvette F-91198, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wdzieczak-Bakala
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR 2301, CNRS avenue de la terrasse, Gif sur Yvette F-91198, 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, Gif sur Yvette F-91198, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.affiliation: Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, LabEx LERMIT, Equipe Labellisée Ligue Contre le Cancer, 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: Univ Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, LabEx LERMIT, Equipe Labellisée Ligue Contre le Cancer, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-92296, France. Electronic address: 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, LabEx LERMIT, Equipe Labellisée Ligue Contre le Cancer, 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: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D019800:Phenol; D012756:Sheep; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D001632:Bibenzyls; C477638:Erianin; D014404:Tubulin; D019800:Phenol
keywords: Antimitotic; AzaisoCA-4; Combretastatin A-4; Cytotoxicity; IsoCA-4; Isoerianin; Tubulin