Inhibitors and promoters of tubulin polymerization: Synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents

• Published in: Bioorganic & medicinal chemistry 2011-04, Vol.19 (8), p.2659-2665
• Main Authors: Dyrager, Christine, Wickström, Malin, Fridén-Saxin, Maria, Friberg, Annika, Dahlén, Kristian, Wallén, Erik A.A., Gullbo, Joachim, Grøtli, Morten, Luthman, Kristina
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Binding Sites; Biological and medical sciences; Cell Line, Tumor; cell structures; chalcone; Chalcones; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; colchicine; Cytotoxicity; Drug Screening Assays, Antitumor; General aspects; Humans; inhibitory concentration 50; Ketones; Läkemedelskemi; Medical sciences; MEDICIN; Medicinal Chemistry; MEDICINE; Molecular modeling; paclitaxel; Pharmacology. Drug treatments; Polymerization; Structure-Activity Relationship; tubulin; Tubulin - agonists; Tubulin - drug effects; Tubulin Modulators - chemical synthesis; Tubulin polymerization
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2011.03.005

A series of dihalogenated chalcones and structurally related dienones were synthesized and evaluated for their antiproliferative activity in 10 different cancer cell lines and for their effect on microtubule assembly. All compounds showed cytotoxic activity, with IC 50 values in the 5–280 μM range depending on the chalcone structure and the cell line. Five of the compounds were found to be tubulin polymerization inhibitors. In contrast, one of the compounds was found to stabilize tubulin to the same extent as the anticancer drug docetaxel. Molecular modeling suggested that the tubulin inhibitors bind to the colchicine binding site of β-tubulin while the novel tubulin stabilization agent seems to interact with the paclitaxel binding site.