Synthesis of hybrid 4-deoxypodophyllotoxin-5-fluorouracil compounds that inhibit cellular migration and induce cell cycle arrest

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• 作者：Xiao-Wen Guan^a ; Xiao-Hui Xu^a ; Shi-Liang Feng^a ; Zhen-Bo Tang^a ; Shi-Wu Chen^a ; ^{chenshw@lzu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Ling Hui^b ; ^c ;
• 关键词：Podophyllotoxin ; 5-Fluorouracil ; Cell cycle arrest ; Cell migration
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：26
• 期：6
• 页码：1561-1566
• 全文大小：1268 K

文摘

A series of deoxypodophyllotoxin–5-fluorouracil hybrid compounds were synthesized, and their cytotoxic activity was evaluated using four human cancer cell lines (HeLa, A549, HCT-8, and HepG2) and the human normal cell line WI-38. The synthesized compounds exhibited greater cytotoxic activity in tumor cells and reduced toxicity in the normal cell line compared with the anticancer drug VP-16 and 5-FU. Additionally, the most potent of these compounds—4′-O-demethyl-4-deoxypodophyllotoxin-4′-yl 4-((6-(2-(5-fluorouracil-yl) acetamido) hexyl) amino)-4-oxobutanoate (compound 22)—induced cell-cycle arrest in the G2/M phase by regulating levels of cdc2, cyclinB1, and p-cdc2 in A549 cells. Furthermore, compound 22 may inhibited the migration of A549 cells via down-regulation of MMP-9 and up-regulation of TIMP-1.