Methylene versus carbonyl bridge in the structure of new tubulin polymerization inhibitors with tricyclic A-rings

  • Bioorg Med Chem. 2016 Nov 15;24(22):6021-6030. doi: 10.1016/j.bmc.2016.09.063.
Iuliana-Monica Moise  1 ,  Elena Bîcu  1 ,  Joëlle Dubois  2 ,  Amaury Farce  3 ,  Benoît Rigo  4 ,  Alina Ghinet  5
Affiliations
  • 1. "Alexandru Ioan Cuza" University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania.
  • 2. Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
  • 3. 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.
  • 4. 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.
  • 5. "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: [email protected].
PMID: 27707624 DOI: 10.1016/j.bmc.2016.09.063
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 GI50 of 25nM against the melanoma MDA-MB-435 cell line.

Keywords
9(10H)Acridone; Antitumor agent; Azaphenothiazine; Iminodibenzyl; Phenothiazine; Phenoxazine; Tubulin inhibitor.