Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers
Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers
复制标题
新型青蒿素衍生物抗肝癌和卵巢癌的结构优化及生物学评价
DOI：
10.1016/j.ejmech.2020.113000
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发表时间：
2021-01-22
影响因子：
6.7
通讯作者：
Liu, Hong
中科院分区：
文献类型：
--
作者：
Zhou, Yu;Li, Xiaoguang;Liu, Hong
近年来，青蒿素及其衍生物对人类肿瘤具有潜在的治疗价值。然而，由于其不良的药代动力学特征，它们的治疗效力是有限的。本课题组前期研究表明，将已获批准的化疗药物美法仑的药效团通过琥珀酸连接体引入青蒿素的基本骨架中，得到的先导化合物ARS 4对人卵巢癌细胞具有良好的毒性，而对正常细胞的细胞毒性较低。其作用机制研究表明，其抑制卵巢癌细胞的生长和增殖，导致S期阻滞、凋亡和迁移抑制。同时，它在动物模型中表现出良好的抗肿瘤活性。本文对该先导化合物ARS 4进行了进一步的结构优化，设计并合成了19个新的衍生物。其中，化合物10-12、15、16、18和19对人肝癌和卵巢癌细胞系表现出强大的细胞毒作用，其对Hep 3B和A2780细胞系的IC 50低于0.86 μ M，其IC 50优于ARS 4的IC 50，其IC 50为上级。四种化合物对化合物（11、15、16和18）进行了体内外抗肿瘤活性研究，结果表明化合物18的抗肿瘤活性最好，不仅能有效抑制7404和Huh 7移植瘤的生长，而且对A2780移植瘤的生长也有很好的抑制作用，并呈剂量依赖性。总之，基于这些积极的结果，这些新的化学结构可能为发现源自青蒿素支架的新型抗肿瘤药物提供新的灵感。(C)2020年由Elsevier Masson SAS出版。
An increasing number of artemisinin (ARS) and its derivatives have been reported for their potential therapeutic value of human cancer. However, their therapeutic potencies are limited owing to their poor pharmacokinetic profiles. Our previous studies showed that a lead compound ARS4 originated from incorporating the pharmacophore of the approved chemotherapeutic agent melphalan into the basic skeleton of artemisinin with a succinic linker exhibited an excellent toxicity to human ovarian cancer cells and low cytotoxicity to normal cells. The mechanism studies demonstrated that it inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis and inhibition of migration. Meanwhile, it exhibited excellent antitumor activities in animal models. Herein, further structure optimization for this lead compound ARS4 was performed and nineteen novel derivatives were designed and synthesized. Among them, compounds 10-12, 15, 16, 18 and 19 demonstrated powerful cytotoxic effects against human liver cancer and ovarian cancer cell lines, with their IC50s below 0.86 mu M against Hep3B and A2780 cell lines, which are superior to that of ARS4. Four compounds (11, 15, 16 and 18) were selected to further evaluate their antitumor activities in in vitro and in vivo ovarian and liver cancer models, the results indicated that compound 18 exhibited the best therapeutic effect, not only effectively inhibited the growth of 7404 xenograft and Huh7 xenograft, but also presented a good dose-dependent inhibition toward the growth of A2780 xenograft. Overall, based on these positive results, these novel chemical structures may provide a new inspiration for the discovery of novel antitumor agents originated from artemisinin scaffolds. (C) 2020 Published by Elsevier Masson SAS.