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Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers

文献类型：期刊论文

作者Zhou, Yu2,3,4; Li, Xiaoguang1; Chen, Kerong2,3; Ba, Qian1; Zhang, Xu2,3; Li, Jingquan1; Wang, Jinfang2,3,4; Wang, Hui1; Liu, Hong2,3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-02-05
卷号211页码:13
关键词Structural optimization Lead compound Artemisinin derivatives Cancer
ISSN号0223-5234
DOI10.1016/j.ejmech.2020.113000
通讯作者Wang, Hui(huiwang@shsmu.edu.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要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 tM 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 dosedependent 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.
WOS关键词DIHYDROARTEMISININ DERIVATIVES ; ANTIMALARIAL ; DIMERS ; MONOMERS ; DESIGN ; SERIES ; MECHANISMS ; APOPTOSIS ; CHALCONE ; LEUKEMIA
资助项目National Natural Science Foundation of China[21672232] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[31401611] ; National Natural Science Foundation of China[8197111150] ; National Natural Science Foundation of China[81672763] ; National Science and Technology Major Project[2017ZX09101002-002-005] ; Science and Technology Commission of Shanghai Municipality[16391903700] ; Science and Technology Commission of Shanghai Municipality[14391901800]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000612147700002
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/295795]  
专题新药研究国家重点实验室
通讯作者Wang, Hui; Liu, Hong
作者单位1.Shanghai Jiao Tong Univ, Ctr Single Cell Omics, Sch Publ Hlth, State Key Lab Oncogenes & Related Genes,Sch Med, Shanghai 200025, Peoples R China
2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai, Peoples R China
3.Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Yu,Li, Xiaoguang,Chen, Kerong,et al. Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,211:13.
APA Zhou, Yu.,Li, Xiaoguang.,Chen, Kerong.,Ba, Qian.,Zhang, Xu.,...&Liu, Hong.(2021).Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,211,13.
MLA Zhou, Yu,et al."Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 211(2021):13.

入库方式： OAI收割

来源：上海药物研究所

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