Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity

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• 作者：Edson dos A. dos Santos ; Ernest Hamel ; Ruoli Bai ; James C. Burnett ; Camila Santos Suniga Tozatti ; Danielle Bogo ; Renata T. Perdomo ; Alex ; ra M.M. Antunes ; M. Matilde Marques ; Maria de F.C. Matos ; D¨ºnis P. de Lima
• 关键词：Diaryl selenide ; Diaryl sulfide ; Combretastatin A-4 ; Tubulin ; Cytotoxicity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 August, 2013
• 年：2013
• 卷：23
• 期：16
• 页码：4669-4673
• 全文大小：851 K

文摘

We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.