Research Papers:

Antivascular and antitumor properties of the tubulin-binding chalcone TUB091

María-Dolores Canela, Sam Noppen, Oskía Bueno, Andrea E. Prota, Katja Bargsten, Gonzalo Sáez-Calvo, María-Luisa Jimeno, Mohammed Benkheil, Domenico Ribatti, Sonsoles Velázquez, María-José Camarasa, J. Fernando Díaz, Michel O. Steinmetz, Eva-María Priego, María-Jesús Pérez-Pérez and Sandra Liekens _

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Oncotarget. 2017; 8:14325-14342. https://doi.org/10.18632/oncotarget.9527

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María-Dolores Canela1, Sam Noppen2, Oskía Bueno1, Andrea E. Prota3, Katja Bargsten3, Gonzalo Sáez-Calvo4, María-Luisa Jimeno5, Mohammed Benkheil2, Domenico Ribatti6, Sonsoles Velázquez1, María-José Camarasa1, J. Fernando Díaz4, Michel O. Steinmetz3, Eva-María Priego1, María-Jesús Pérez-Pérez1, Sandra Liekens2

1Instituto de Química Médica (IQM-CSIC), Madrid, Spain

2KU Leuven – University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium

3Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland

4Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain

5Centro de Química Orgánica Lora-Tamayo (CENQUIOR-CSIC), Madrid, Spain

6Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, National Cancer Institute “Giavanni Paolo II”, Bari, Italy

Correspondence to:

Sandra Liekens, email: [email protected]

María-Jesús Pérez-Pérez, email: [email protected]

Keywords: cancer, drug research, tubulin, vascular-disrupting

Received: January 15, 2016     Accepted: May 01, 2016     Published: May 20, 2016


We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.

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