title: Novel benzopyridothiadiazepines as potential active antitumor agents.
abstract: The synthesis of novel thiadiazepine derivatives, that could be considered as constraint analogues of E-7010, are reported. These molecules were evaluated for their antiproliferative activity toward the murine L1210 leukemia cell line. Flow cytometric studies performed on L1210 cells with the most cytotoxic compounds showed an accumulation of the cells in the G2/M phases of the cell cycle with a significant percentage of tetraploid cells (8N DNA content). Submicromolar cytotoxicities were observed with compounds 2b, 4b, 4e, 4g, and 4i. Two of them, compounds 2b and 4b, were found to be potent inhibitors of tubulin polymerization with IC50 of respectively 3.8 and 2.4 microM compared to 2.4 microM for desoxypodophyllotoxin. A 4-methoxyphenylethyl substitution on the pyridinyl nitrogen of the benzopyridothiadiazepine was found to be essential for the antiproliferative activity. The in vitro activities of compounds 2b and 4b make benzopyridothiadiazepine dioxides a promising new class of tubulin binders which warrant further in vivo evaluation.
authors.affiliation: Laboratoire de Chimie Thérapeutique EA1043, Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du Professeur Laguesse, B.P. 83 59006 Lille Cedex, France. nlebegue@pharma.univ-lille2.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebegue
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gallet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Flouquet
authors.forename: Pascal
authors.initials: P
authors.lastname: Carato
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Pascal
authors.initials: P
authors.lastname: Berthelot
mesh_terms: D000627:Aminophenols / Q000737:chemistry; D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000627:Aminophenols; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D003499:Cyclic S-Oxides; D006575:Heterocyclic Compounds, 3-Ring; D013449:Sulfonamides; D013841:Thiazepines; D050257:Tubulin Modulators; C507030:1-(4-methoxyphenylethyl)-6-methylbenzo(c)-1,2-dihydropyrido(2,3-f)(1,2,5)thiadiazepine 5,5-dioxide; C079199:E 7010; D000096926:Benzenesulfonamides