title: Methylene versus carbonyl bridge in the structure of new tubulin polymerization inhibitors with tricyclic A-rings.
abstract: The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the "CH2" bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6-8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50of 25nM against the melanoma MDA-MB-435 cell line.
authors.affiliation: "Alexandru Ioan Cuza" University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania.
authors.forename: Iuliana-Monica
authors.initials: IM
authors.lastname: Moise
authors.affiliation: "Alexandru Ioan Cuza" University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania.
authors.forename: Elena
authors.initials: E
authors.lastname: Bîcu
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.affiliation: Inserm U995, LIRIC, Université de Lille, CHRU de Lille, Faculté de médecine-Pôle recherche, Place Verdun, F-59045 Lille Cedex, France; Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3 Rue du Pr Laguesse, B.P. 83, F-59006 Lille, France.
authors.forename: Amaury
authors.initials: A
authors.lastname: Farce
authors.affiliation: Inserm U995, LIRIC, Université de Lille, CHRU de Lille, Faculté de médecine-Pôle recherche, Place Verdun, F-59045 Lille Cedex, France; Hautes Etudes d'Ingénieur (HEI), Groupe HEI-ISA-ISEN, UCLille, Laboratoire de Pharmacochimie, 13 rue de Toul, F-59046 Lille, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Rigo
authors.affiliation: "Alexandru Ioan Cuza" University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania; Inserm U995, LIRIC, Université de Lille, CHRU de Lille, Faculté de médecine-Pôle recherche, Place Verdun, F-59045 Lille Cedex, France; Hautes Etudes d'Ingénieur (HEI), Groupe HEI-ISA-ISEN, UCLille, Laboratoire de Pharmacochimie, 13 rue de Toul, F-59046 Lille, France. Electronic address: alina.ghinet@hei.fr.
authors.forename: Alina
authors.initials: A
authors.lastname: Ghinet
mesh_terms: D000970:Antineoplastic Agents / 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; D008958:Models, Molecular; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D010640:Phenothiazines; D014404:Tubulin; C031637:phenothiazine
keywords: 9(10H)Acridone; Antitumor agent; Azaphenothiazine; Iminodibenzyl; Phenothiazine; Phenoxazine; Tubulin inhibitor