Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
复制标题
天然产物吴茱萸碱的支架跳跃：发现一种具有优异抗结肠癌功效的新型抗肿瘤支架。
DOI：
10.1021/acs.jmedchem.9b01626
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发表时间：
2020-01-23
影响因子：
7.3
通讯作者：
Sheng, Chunquan
中科院分区：
文献类型：
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作者：
Wang, Lei;Fang, Kun;Sheng, Chunquan
受天然产物吴茱萸碱的启发，采用骨架跳跃法设计了一种新型吲哚吡嗪喹唑啉酮抗肿瘤骨架。结构-活性关系研究导致发现化合物15 j，其显示出针对HCT 116细胞系的低纳摩尔抑制活性。进一步的抗肿瘤机制研究表明，化合物15 j通过抑制拓扑异构酶1（Top1）和微管蛋白的双重作用，诱导细胞凋亡，使细胞周期阻滞于G2期。化合物15 j的季铵盐（化合物15 js）在具有低毒性的HCT 116异种移植模型中表现出优异的体内抗肿瘤活性（TGI = 66.6%）。吲哚并吡嗪并喹唑啉酮衍生物是一种具有多靶点的新型抗肿瘤药物。
Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 (Top1) and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.