Synthesis and biological evaluation of 4 arylcoumarin analogues as tubulin-targeting antitumor agents

Publication date: Available online 27 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Peggoty Mutai, Gilles Breuzard, Alessandra Pagano, Diane Allegro, Vincent Peyrot, Kelly Chibale
The synthesis of twenty-six 4-arylcoumarin analogues of combretastatin A-4 (CA-4) led to the identification of two new compounds (25 and 26) with strong cytotoxic activity. Both compounds had a high cytotoxic effect on a CA-4-resistant colon adenocarcinoma cell line (HT29D4). The compounds affected cell cycle progression characterized by a mitotic block. The activity of these compounds against microtubules both in vitro and in cells was examined and both compounds were found to potently inhibit in vitro microtubule formation via a sub-stoichiometric mode like CA-4. By immunofluorescence, it was observed that both compounds induced strong microtubule network disruption. Our results provide a strong experimental basis to develop new potent anti-tubulin molecules targeting CA-4-resistant cancer cells.

Graphical abstract

http://ift.tt/2jg8hSX