Triethylated chromones with substituted naphthalenes as tubulin inhibitors

详细信息    查看全文

• 作者：Kyoko Nakagawa-Goto^a ; ^b ; ^{kngoto@p.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Yukako Taniguchi^a ; Yurie Watanabe^a ; Akifumi Oda^a ; Emika Ohkoshi^b ; Ernest Hamel^c ; Kuo-Hsiung Lee^b ; ^d ; Masuo Goto^b ; ^{goto@med.unc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Triethylated chromones ; Naphthalene ; Mitotic inhibitors
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：24
• 期：22
• 页码：6048-6057
• 全文大小：2462 K

文摘

Previously synthesized 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (1, TEDB-TB) and 2-(naphth-1′-yl)-6,8,8-triethyldesmosdumotin B (2) showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs (3–5) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound 6, a 4′-acetoxynaphthalen-1′-yl derivative, displayed the most potent antiproliferative activity (IC₅₀ 0.2–5.7 μM). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin.