Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment

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• 作者：Zhishan Cui^a ; ^b ; ^&dagger ; ; Xi Li^b ; ^&dagger ; ; Lulu Li^a ; ^b ; Bin Zhang^b ; ^{binzhang86@126.com" class="auth_mail" title="E-mail the corresponding author} ; Chunmei Gao^a ; ^b ; ^{chunmeigao@sz.tsinghua.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Yuzong Chen^c ; Chunyan Tan^a ; ^b ; Hongxia Liu^a ; ^b ; Weiyi Xie^b ; Ti Yang^b ; Yuyang Jiang^a ; ^b ; ^d
• 关键词：Src ; MEK ; Kinase inhibitor ; Acridine ; Antitumor ; Apoptosis
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：24
• 期：2
• 页码：261-269
• 全文大小：1289 K

文摘

Clinical studies have shown enhanced anticancer effects of combined inhibition of Src and MEK kinases. Development of multi-target drugs against Src and MEK is of potential therapeutic advantage against cancers. As a follow-up of our previous studies, and by using molecular docking method, we designed and synthesized a new series of 9-anilinoacridines containing phenyl-urea moieties as potential novel dual Src and MEK inhibitors. The anti-proliferative assays against K562 and HepG-2 tumor cells showed that most of the derivatives displayed good cytotoxicity in vitro. In particular, kinase inhibition assays showed that compound rong class="boldFont">8mrong> inhibited Src (59.67%) and MEK (43.23%) at 10 μM, and displayed moderate inhibitory activity against ERK and AKT, the downstream effectors of both Src and MEK. Moreover, compound rong class="boldFont">8mrong> was found to induce K562 cells apoptosis. Structure–activity relationships of these derivatives were analyzed. Our study suggested that acridine scaffold, particularly compound rong class="boldFont">8mrong>, is of potential interest for developing novel multi-target Src and MEK kinase inhibitors.