Identification of 3-(benzazol-2-yl)quinoxaline derivatives as potent anticancer compounds: Privileged structure-based design, synthesis, and bioactive evaluation in vitro and in vivo.
Identification of 3-(benzazol-2-yl)quinoxaline derivatives as potent anticancer compounds: Privileged structure-based design, synthesis, and bioactive evaluation in vitro and in vivo.
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DOI：
10.1016/j.ejmech.2019.01.004
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发表时间：
2019-03
影响因子：
6.7
通讯作者：
Qing-qing Liu;Ke Lu;Haiping Zhu;Shi-Lin Kong;Jing-Mei Yuan;Guo-Hai Zhang;Nan Chen;Chendi Gu;Cheng-Xue Pan;Dong-Liang Mo;Gui-Fa Su
中科院分区：
文献类型：
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作者：
Qing-qing Liu;Ke Lu;Haiping Zhu;Shi-Lin Kong;Jing-Mei Yuan;Guo-Hai Zhang;Nan Chen;Chendi Gu;Cheng-Xue Pan;Dong-Liang Mo;Gui-Fa Su
受许多已知的靶向DNA或拓扑异构酶I的抗肿瘤化合物的共同结构特征的启发，通过两个重要的特权结构单元-喹喔啉和噻唑的组合，设计了基于3-（苯并唑-2-基）-喹喔啉的支架。合成了30个新的3-（苯并唑-2-基）-喹喔啉衍生物，并对其生物活性进行了评价。MTT法显示大部分化合物对MGC-803、HepG 2、A549、HeLa、T-24和WI-38细胞株具有中等至强的抑制增殖作用。3-（苯并恶唑-2-基）-2-（N-3-二甲氨基丙基）氨基喹喔啉（12 a）显示出最强的细胞毒性，对5种测试的癌症和1种正常细胞系的IC 50值范围为1.49至10.99 μM。琼脂糖凝胶电泳分析表明，12 a不与完整的DNA相互作用，而是通过Topo I介导的DNA解旋强烈抑制拓扑异构酶I（Topo I）发挥其抗癌活性。分子模拟研究表明，12 a与DNA和Topo I的相互作用方式独特。对12 ain MGC-803细胞的详细生物学研究表明，12 a可使细胞周期阻滞于G2期，引起活性氧（ROS）的产生，细胞内Ca ~（2+）的波动，线粒体膜电位（Δ Km）的丧失。Western Blot分析表明，12 a处理可显著上调促凋亡蛋白巴克、Bax和Bim的水平，下调抗凋亡蛋白Bcl-2和Bcl-xl的水平，并增加细胞周期蛋白B1和CDKs抑制剂p21、细胞色素c、caspase-3、caspase-9及其活化形式在MGC-803细胞中以剂量依赖性方式通过caspase依赖性内源性caspase介导的途径诱导细胞凋亡。在MGC-803异种移植肿瘤模型中的研究表明，低至6 mg/kg的剂量12 a可显著降低体内肿瘤生长，毒性低。3-（苯并唑-2-基）喹喔啉支架具有制备方便、体内抗肿瘤活性强等优点，是一种很有前途的新型化学实体。
Inspired by the common structural characteristics of numerous known antitumor compounds targeting DNA or topoisomerase I, 3-(benzazol-2-yl)-quinoxaline-based scaffold was designed via the combination of two important privileged structure units —quinoxaline and benzazole. Thirty novel 3-(benzazol-2-yl)-quinoxaline derivatives were synthesized and evaluated for their biological activities. The MTT assay indicated that most compounds possessed moderate to potent antiproliferation effects against MGC-803, HepG2, A549, HeLa, T-24 and WI-38 cell lines. 3-(Benzoxazol- -2-yl)-2-(N-3-dimethylaminopropyl)aminoquinoxaline (12a) exhibited the most potent cytotoxicity, with IC50values ranging from 1.49 to 10.99 μM against the five tested cancer and one normal cell line. Agarose-gel electrophoresis assays suggested that12adid not interact with intact DNA, but rather it strongly inhibited topoisomerase I (Topo I) via Topo I-mediated DNA unwinding to exert its anticancer activity. The molecular modeling study indicated that12aadopt a unique mode to interact with DNA and Topo I. Detailed biological study of12ain MGC-803 cells revealed that12acould arrest the cell cycle in G2 phase, inducing the generation of reactive oxygen species (ROS), the fluctuation of intracellular Ca2+, and the loss of mitochondrial membrane potential (ΔΨm). Western Blot analysis indicated that12a-treatment could significantly up-regulate the levels of pro-apoptosis proteins Bak, Bax, and Bim, down-regulate anti-apoptosis proteins Bcl-2 and Bcl-xl, and increase levels of cyclin B1 and CDKs inhibitor p21, cytochromec, caspase-3, caspase-9 and their activated form in MGC-803 cells in a dose-dependent manner to induce cell apoptosis via a caspase-dependent intrinsic mitochondria-mediated pathway. Studies in MGC-803 xenograft tumors models demonstrated that12acould significantly reduce tumor growthin vivoat doses as low as 6 mg/kg with low toxicity. Its convenient preparation and potent anticancer efficacyin vivomakes the 3-(benzazol-2-yl)quinoxaline scaffold a promising new chemistry entity for the development of novel chemotherapeutic agents.