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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

Romagnoli, Romeo, Baraldi, Pier Giovanni, Lopez-Cara, Carlota, Cruz-Lopez, Olga, Carrion, Maria Dora, Kimatrai Salvador, Maria, Bermejo, Jaime, Estévez, Sara, Estévez, Francisco, Balzarini, Jan, Brancale, Andrea, Ricci, Antonio, Chen, Longchuan, Kim, Jae Gwan and Hamel, Ernest 2011. 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. Chemmedchem 6 (10) , pp. 1841-1853. 10.1002/cmdc.201100279

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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 (IC50=16–24 nm), and interacts strongly with tubulin by binding to the colchicine site. Sub-G1 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: antiproliferative agents; apoptosis; caspase activation; colchicine binding site; tubulin
Publisher: Wiley-Blackwell
ISSN: 1860-7179
Last Modified: 04 Jun 2017 02:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/7479

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