Combretastatin-like chalcones as inhibitors of microtubule polymerisation. Part 2: Structure-based discovery of alpha-aryl chalcones

• Published in: Bioorganic & medicinal chemistry 2009-11, Vol.17 (22), p.7711-7722
• Main Authors: Ducki, Sylvie, Mackenzie, Grant, Greedy, Ben, Armitage, Simon, Chabert, Jérémie Fournier Dit, Bennett, Elizabeth, Nettles, Jim, Snyder, James P., Lawrence, Nicholas J.
• Format: Article
• Language: English
• Subjects: Algorithms; Anticancer; Antineoplastic agents; Antivascular; Bibenzyls - chemical synthesis; Bibenzyls - chemistry; Bibenzyls - pharmacology; Binding Sites; Biological and medical sciences; Cell Line; Chalcone; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Colchicine; Colchicine - analogs & derivatives; Colchicine - chemical synthesis; Colchicine - chemistry; Colchicine - pharmacology; Combretastatin; Docking; Drug Discovery; General aspects; Humans; Hydrocarbons, Cyclic - chemical synthesis; Hydrocarbons, Cyclic - chemistry; Hydrocarbons, Cyclic - pharmacology; Medical sciences; Microtubules - drug effects; Microtubules - metabolism; Pharmacology. Drug treatments; Podophyllotoxin; Structure-Activity Relationship; Tubulin; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.09.044

Tubulin is an important molecular target in cancer chemotherapy. Antimitotic agents able to bind to the protein are currently under study, commonly used in the clinic to treat a variety of cancers and/or exploited as probes to investigate the protein’s structure and function. Here we report the binding modes for a series of colchicinoids, combretastatin A4 and chalcones established from docking studies carried out on the structure of tubulin in complex with colchicine. The proposed models, in agreement with published biochemical data, show that combretastatin A4 binds to the colchicine site of β-tubulin and that chalcones assume an orientation similar to that of podophyllotoxin. The models can be used to design a new class of podophyllotoxin mimics, the α-aryl chalcones, capable of binding to the colchicine-binding site of β-tubulin with higher affinity.