Synthesis and Biological Evaluation of N-[2-(4-Hydroxyphenylamino)-pyridin-3-yl]-4-methoxy-benzenesulfonamide (ABT-751) Tricyclic Analogues as Antimitotic and Antivascular Agents with Potent in Vivo Antitumor Activity

  • J Med Chem. 2016 Sep 22;59(18):8422-40. doi: 10.1021/acs.jmedchem.6b00847.
Zacharie Segaoula  1  2 ,  Julien Leclercq  1 ,  Valérie Verones  1 ,  Nathalie Flouquet  1 ,  Marie Lecoeur  3 ,  Lionel Ach  3 ,  Nicolas Renault  4 ,  Amélie Barczyk  4 ,  Patricia Melnyk  1 ,  Pascal Berthelot  1 ,  Xavier Thuru  1 ,  Nicolas Lebegue  1
Affiliations
  • 1. Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
  • 2. Oncovet Clinical Research , SIRIC ONCOLille, Parc Eurasante, Rue du Dr Alexandre Yersin, F-59120 Loos, France.
  • 3. Univ. Lille, CHU Lille , EA 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000 Lille, France.
  • 4. Univ. Lille, Inserm, CHU Lille , U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France.
PMID: 27538123 DOI: 10.1021/acs.jmedchem.6b00847
Abstract

Benzopyridothiadiazepine (2a) and benzopyridooxathiazepine (2b) were modified to produce tricyclic quinazolinone 15-18 or benzothiadiazine 26-27 derivatives. These compounds were evaluated in cytotoxicity and tubulin inhibition assays and led to potent inhibitors of tubulin polymerization. N-[2(4-Methoxyphenyl)ethyl]-1,2-dihydro-pyrimidino[2,1-b]quinazolin-6-one (16a) exhibited the best in vitro cytotoxic activity (GI50 10-66.9 nM) against the NCI 60 human tumor cell line and significant potency against tubulin assembly (IC50 0.812 μM). In mechanism studies, 16a was shown to block cell cycle in G2/M phase and to disrupt microtubule formation and displayed good antivascular properties as inhibition of cell migration, invasion, and endothelial tube formation. Compound 16a was evaluated in C57BL/6 mouse melanoma B16F10 xenograft model to validate its antitumor activity, in comparison with reference ABT-751 (1). Compound 16a displayed strong in vivo antitumor and antivascular activities at a dose of 5 mg/kg without obvious toxicity, whereas 1 needed a 10-fold higher concentration to reach similar effects.