2. Academic Validation
  3. Methylene versus carbonyl bridge in the structure of new tubulin polymerization inhibitors with tricyclic A-rings

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

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: alina.ghinet@hei.fr.
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.

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