Design, synthesis, and biological evaluation of novel trimethoxyindole derivatives derived from natural products
Design, synthesis, and biological evaluation of novel trimethoxyindole derivatives derived from natural products
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天然产物新型三甲氧基吲哚衍生物的设计、合成和生物学评价
DOI：
10.1007/s00706-019-02466-8
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发表时间：
2019-08-01
影响因子：
1.8
通讯作者：
Wu, Yuelin
中科院分区：
文献类型：
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作者：
Lu, Fangliu;Chen, Baobao;Wu, Yuelin
摘要龙眼肉碱是一种天然生物碱，具有多种生物活性。本研究利用骨架跳跃策略设计合成了六个含吲哚结构的类似物。它们的抗肿瘤活性优于母体胡椒碱，对正常细胞无明显毒性。其中，3-氯-1-（5，6，7-三甲氧基-1-甲基-1H-吲哚-2-羰基）-5，6-二氢吡啶-2（1H）-酮的体外抗肿瘤活性最好，对4种肿瘤细胞的IC 50值提高了4-8倍。在A549肺癌异种移植物模型中，其显示出54.6%的肿瘤生长抑制，这远高于母体piperlongumine（38.3%）并且与阳性药物阿霉素（53.3%）相当。吲哚-piperlongumine为抗癌药物的发现提供了一个新的先导化合物。
AbstractPiperlongumine, a natural alkaloid, is reported to possess various biological activities. In this study, six analogs with indole moiety have been designed and synthesized using scaffold hopping strategy. They exhibited better antitumor activities than the parent piperlongumine without apparent toxicity in normal cells. Among them, 3-chloro-1-(5,6,7-trimethoxy-1-methyl-1H-indole-2-carbonyl)-5,6-dihydropyridin-2(1H)-one showed the best in vitro antitumor activity with the IC50value improved in 4–8-fold against four cancer cell lines. In an A549 lung cancer xenograft model, it exhibited a tumor growth inhibition of 54.6%, which is much higher than that of parent piperlongumine (38.3%) and comparable to the positive drug doxorubicin (53.3%). The indole–piperlongumine provides a novel lead compound for anticancer drug discovery.Graphic abstract