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_50s below 0.86 μM 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.

越来越多的青蒿素 (ARS) 及其衍生物因其对人类癌症的潜在治疗价值而被报道。然而，由于其较差的药代动力学特征，它们的治疗效力受到限制。我们之前的研究表明，先导化合物ARS4源于将批准的化疗药物美法仑的药效团与琥珀酸接头结合到青蒿素的基本骨架中，对人卵巢癌细胞表现出优异的毒性，对正常细胞的细胞毒性较低。机制研究表明，它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优异的抗肿瘤活性。在此，对该先导化合物ARS4进行了进一步的结构优化，并设计并合成了 19 种新型衍生物。其中，化合物10-12，15，16，18和19对人肝癌和卵巢癌细胞系显示出强大的细胞毒作用，其对 Hep3B 和 A2780 细胞系的 IC ₅₀低于 0.86 μM，优于ARS4。选择了4种化合物（11、15、16和18）进一步评估了它们在体外和体内卵巢癌和肝癌模型中的抗肿瘤活性，结果表明化合物18表现出最好的治疗效果，不仅能有效抑制 7404 异种移植物和 Huh7 异种移植物的生长，而且对 A2780 异种移植物的生长也呈现出良好的剂量依赖性抑制作用。总的来说，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。