Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted iso combretastatin A-4 analogs

Evelia Rasolofonjatovo (1) , Jérome Bignon (1) , Olivier Provot (1) , Abdallah Hamze (1) , Jordi Rodrigo (1) , Jérôme Bignon (2) , Joanna Wdzieczak-Bakala (2) , Christine Lenoir (2) , Déborah Desravines (2) , Joëlle Dubois (2) , Jean-Daniel Brion (1) , Mouad Alami (1)

1 BioCIS - Biomolécules : Conception, Isolement, Synthèse
2 ICSN - Institut de Chimie des Substances Naturelles

A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogues according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on -tubulin.

Mots clés: Cancer; Apoptosis; Cytotoxicity; Tubulin; isoCA-4; Benzoxepin; Combretastatin

Domaines: Chimie thérapeutique; Chimie organique

Evelia Rasolofonjatovo, Jérome Bignon, Olivier Provot, Abdallah Hamze, Jordi Rodrigo, et al.. Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted iso combretastatin A-4 analogs. European Journal of Medicinal Chemistry, 2013, 62, pp.28-39. ⟨10.1016/j.ejmech.2012.12.042⟩. ⟨hal-02394390⟩