title: Antivascular and antitumor properties of the tubulin-binding chalcone TUB091.
abstract: 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.
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
authors.forename: María-Dolores
authors.initials: MD
authors.lastname: Canela
authors.affiliation: KU Leuven - University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
authors.forename: Sam
authors.initials: S
authors.lastname: Noppen
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
authors.forename: Oskía
authors.initials: O
authors.lastname: Bueno
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Prota
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Bargsten
authors.affiliation: Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Sáez-Calvo
authors.affiliation: Centro de Química Orgánica Lora-Tamayo (CENQUIOR-CSIC), Madrid, Spain.
authors.forename: María-Luisa
authors.initials: ML
authors.lastname: Jimeno
authors.affiliation: KU Leuven - University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Benkheil
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, National Cancer Institute "Giavanni Paolo II", Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Velázquez
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.affiliation: Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
authors.forename: Eva-María
authors.initials: EM
authors.lastname: Priego
authors.affiliation: Instituto de Química Médica (IQM-CSIC), Madrid, Spain.
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.affiliation: KU Leuven - University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002599:Chalcone / Q000494:pharmacology*; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D047188:Chalcones; D004151:Dipeptides; D011355:Prodrugs; C000623111:TUB091; C000623112:TUB099; D014404:Tubulin; D050257:Tubulin Modulators; D002599:Chalcone
keywords: cancer; drug research; tubulin; vascular-disrupting