title: Substituted 2-(3',4',5'-trimethoxybenzoyl)-benzo[b]thiophene derivatives as potent tubulin polymerization inhibitors.
abstract: The central role of microtubules in cell division and mitosis makes them a particularly important target for anticancer agents. On our early publication, we found that a series of 2-(3',4',5'-trimethoxybenzoyl)-3-aminobenzo[b]thiophenes exhibited strong antiproliferative activity in the submicromolar range and significantly arrested cells in the G2-M phase of the cell cycle and induced apoptosis. In order to investigate the importance of the amino group at the 3-position of the benzo[b]thiophene skeleton, the corresponding 3-unsubstituted and methyl derivatives were prepared. A novel series of inhibitors of tubulin polymerization, based on the 2-(3,4,5-trimethoxybenzoyl)-benzo[b]thiophene molecular skeleton with a methoxy substituent at the C-4, C-5, C-6 or C-7 position on the benzene ring, was evaluated for antiproliferative activity against a panel of five cancer cell lines, for inhibition of tubulin polymerization and for cell cycle effects. Replacing the methyl group at the C-3 position resulted in increased activity compared with the corresponding 3-unsubstituted counterpart. The structure-activity relationship established that the best activities were obtained with the methoxy group placed at the C-4, C-6 or C-7 position. Most of these compounds exhibited good growth inhibition activity and arrest K562 cells in the G2-M phase via microtubule depolymerization.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy. rmr@unife.it
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Maria Dora
authors.initials: MD
authors.lastname: Carrion
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.forename: Manlio
authors.initials: M
authors.lastname: Tolomeo
authors.forename: Stefania
authors.initials: S
authors.lastname: Grimaudo
authors.forename: Antonietta
authors.initials: A
authors.lastname: Di Cristina
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Pipitone
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000818:Animals; D000840:Anisoles / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000840:Anisoles; D000970:Antineoplastic Agents; D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators