Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: Synthesis and biological evaluation of antivascular activity

• Published in: Bioorganic & medicinal chemistry 2009-11, Vol.17 (22), p.7698-7710
• Main Authors: Ducki, Sylvie, Rennison, David, Woo, Meiko, Kendall, Alexander, Chabert, Jérémie Fournier Dit, McGown, Alan T., Lawrence, Nicholas J.
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antivascular; Bibenzyls - chemical synthesis; Bibenzyls - chemistry; Bibenzyls - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Chalcone; Chalcones - chemical synthesis; Chalcones - chemistry; Chalcones - pharmacology; Colchicine; Combretastatin; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; General aspects; Humans; K562 Cells; Medical sciences; Microtubules - drug effects; Microtubules - metabolism; Neovascularization, Physiologic - drug effects; Pharmacology. Drug treatments; SD400; Structure-Activity Relationship; Tubulin; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.09.039

The α-methyl chalcone SD400 is a potent inhibitor of tubulin assembly and possesses potent anticancer activity. Various chalcone analogues were synthesized and evaluated for their cell growth inhibitory properties against the K562 human chronic myelogenous leukemia cell line (SD400, IC 50 0.21 nM; combretastatin A4 CA4, IC 50 2.0 nM). Cell cycle analysis by flow cytometry indicated that these agents are antimitotic (SD400, 83% of the cells are in G 2/M phase; CA4 90%). They inhibit tubulin assembly at low concentration (SD400, IC 50 0.46 μM; CA4, 0.10 μM) and compete with [ 3H]colchicine for binding to tubulin (8% [ 3H]colchicine remained bound to tubulin after competition with SD400 or CA4). Upon treatment with SD400, remarkable cell shape changes were elicited in HUVEC cells, consistent with vasculature damaging activity.