title: 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.
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.
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.|Oncovet Clinical Research , SIRIC ONCOLille, Parc Eurasante, Rue du Dr Alexandre Yersin, F-59120 Loos, France.
authors.forename: Zacharie
authors.initials: Z
authors.lastname: Segaoula
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Leclercq
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Verones
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Flouquet
authors.affiliation: Univ. Lille, CHU Lille , EA 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000 Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lecoeur
authors.affiliation: Univ. Lille, CHU Lille , EA 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, F-59000 Lille, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Ach
authors.affiliation: Univ. Lille, Inserm, CHU Lille , U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renault
authors.affiliation: Univ. Lille, Inserm, CHU Lille , U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Barczyk
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Melnyk
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Berthelot
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Thuru
authors.affiliation: Univ. Lille, Inserm, CHU Lille , UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebegue
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D020533:Angiogenesis Inhibitors; D050256:Antimitotic Agents; D001581:Benzothiadiazines; D052999:Quinazolinones; D013449:Sulfonamides; D014404:Tubulin; D050257:Tubulin Modulators; D000096926:Benzenesulfonamides; C490492:ABT751