title: Studies on phenothiazines: New microtubule-interacting compounds with phenothiazine A-ring as potent antineoplastic agents.
abstract: New phenothiazine derivatives 6-20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2'-fluoro-4'-methoxy substitution in compound 6 and the 2'-trifluoromethyl-4'-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6-8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke's type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.
authors.affiliation: Department of Organic Chemistry, 'Al. I. 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.
authors.forename: Alina
authors.initials: A
authors.lastname: Ghinet
authors.affiliation: Department of Organic Chemistry, 'Al. I. 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: 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: 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: Germain
authors.initials: G
authors.lastname: Homerin
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: 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: Department of Organic Chemistry, 'Al. I. Cuza' University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania. Electronic address: elena@uaic.ro.
authors.forename: Elena
authors.initials: E
authors.lastname: Bîcu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D010640:Phenothiazines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010640:Phenothiazines; D014404:Tubulin; D050257:Tubulin Modulators
keywords: Anticancer agent; Microtubule-targeting agent; Phenothiazine; Tubulin