title: Benzopyridooxathiazepine derivatives as novel potent antimitotic agents.
abstract: Herein, we describe the structure-activity relationship study of a new 1-(arylalkyl)-11H-benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine 5,5-dioxide series of antimitotic agents. The pharmacological results obtained from previous works allowed us to identify compound 1 as a new cytotoxic agent inhibiting tubulin polymerization. We have undertaken the synthesis of its non-methylated analogue 7 and have extended our investigations to a novel, structurally related benzopyridooxathiazepine dioxide series. Among all analogues synthesized in this study, compound 10b was the most promising, being 12-fold more potent than compound 1. Its activity over a panel of five tumoral cell lines was in the nanomolar range for all of the histological types tested and flow cytometric studies performed on L1210 cells 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). This interesting pharmacological profile, resulting from inhibition of tubulin polymerization, encouraged us to perform preliminary in vivo studies.
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.
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: Pascal
authors.initials: P
authors.lastname: Berthelot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebegue
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D013841:Thiazepines; D050257:Tubulin Modulators