Structural optimization and biological evaluation for novel artemisinin derivatives against liver and ovarian cancers
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 IC
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Funding
National Major Science and Technology Projects of China Grant 2017ZX09101002-002-005National Natural Science Foundation of China Grant 21632008National Natural Science Foundation of China Grant 21672232National Natural Science Foundation of China Grant 31401611National Natural Science Foundation of China Grant 81620108027National Natural Science Foundation of China Grant 81672763National Natural Science Foundation of China Grant 8197111150Science and Technology Commission of Shanghai Municipality Grant 14391901800Science and Technology Commission of Shanghai Municipality Grant 16391903700