title: Synthesis and antitumor molecular mechanism of agents based on amino 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan: inhibition of tubulin and induction of apoptosis.
abstract: Induction of apoptosis is a promising strategy that could lead to the discovery of new molecules active in cancer chemotherapy. This property is generally observed when cells are treated with agents that target microtubules, dynamic structures that play a crucial role in cell division. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. A new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular skeleton, with the amino group placed at different positions on the benzene ring, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell-cycle effects. The methoxy substitution pattern on the benzene portion of the benzo[b]furan moiety played an important role in affecting antiproliferative activity. In the series of 5-amino derivatives, the greatest inhibition of cell growth occurred if the methoxy substituent is placed at the C6 position, whereas C7 substitution decreases potency. The most promising compound in this series is 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-5-amino-6-methoxybenzo[b]furan (3 h), which inhibits cancer cell growth at nanomolar concentrations (IC(50) =16-24 nM), and interacts strongly with tubulin by binding to the colchicine site. Sub-G(1) apoptotic cells in cultures of HL-60 and U937 cells were observed by flow cytometric analysis after treatment with 3 h in a concentration-dependent manner. We also show that compound 3 h induces apoptosis by activation of caspase-3, -8, and -9, and this is associated with cytochrome c release from mitochondria. The introduction of an α-bromoacryloyl group increased antiproliferative activity with respect to the parent amino derivatives.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 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: Carlota
authors.initials: C
authors.lastname: Lopez-Cara
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.forename: Maria Dora
authors.initials: MD
authors.lastname: Carrion
authors.forename: Maria
authors.initials: M
authors.lastname: Kimatrai Salvador
authors.forename: Jaime
authors.initials: J
authors.lastname: Bermejo
authors.forename: Sara
authors.initials: S
authors.lastname: Estévez
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Antonio
authors.initials: A
authors.lastname: Ricci
authors.forename: Longchuan
authors.initials: L
authors.lastname: Chen
authors.forename: Jae Gwan
authors.initials: JG
authors.lastname: Kim
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D003078:Colchicine / Q000737:chemistry; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C569481:(5-amino-3-methyl-6-methoxybenzo(b)furan-2-yl)(3,4,5-trimethoxyphenyl) methanone; D000840:Anisoles; D000970:Antineoplastic Agents; D001572:Benzofurans; D014404:Tubulin; D050257:Tubulin Modulators; D020169:Caspases; C105430:benzofuran; D003078:Colchicine