Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Faculty of Pharmacy, School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an, Shaanxi 710021, China.
J Med Chem. 2023 Jun 22;66(12):8066-8085. doi: 10.1021/acs.jmedchem.3c00396. Epub 2023 Jun 12.
Recently, artemisinin and derivatives have been revealed to possess encouraging antitumor activity. Herein, we integrated the antitumor advantages of artesunate and platinum drugs to construct novel Pt-artesunate dual-action and triple-action complexes. Most derivatives, especially , displayed broad-spectrum and potent antitumor activities against a number of cancer cell lines. Compound displayed potent antimetastasis and anticlonogenic activities, efficiently induced autophagic cell death and apoptosis, and arrested the cell cycle at both S and G2/M phases. More importantly, it displayed remarkable antitumor efficacy in the A549 xenograft model (TGI = 53.4%; 6 μmol/kg) with low toxicity. In addition to the antitumor application, showed potent antimalarial activity in malarial-infected mice model and obviously alleviated malarial-related multiorgan injury. This conjugation greatly improved safety, especially reducing the platinum drugs' nephrotoxicity. Taken together, this study highlighted the therapeutic potential of Pt-artesunate complexes as antitumor and antimalarial agents.
最近，青蒿素及其衍生物被发现具有令人鼓舞的抗肿瘤活性。在此，我们整合了青蒿琥酯和铂类药物的抗肿瘤优势，构建了新型的 Pt-青蒿琥酯双重和三重作用的配合物。大多数衍生物，特别是 ，对多种癌细胞系表现出广谱和强效的抗肿瘤活性。化合物 显示出强大的抗转移和抗集落形成活性，有效诱导自噬性细胞死亡和细胞凋亡，并将细胞周期阻滞在 S 和 G2/M 期。更重要的是，它在 A549 异种移植模型中表现出显著的抗肿瘤疗效（TGI = 53.4%；6 μmol/kg），且毒性较低。除了抗肿瘤应用外， 在疟原虫感染的小鼠模型中还显示出强大的抗疟活性，并明显减轻了与疟疾相关的多器官损伤。这种结合大大提高了安全性，特别是降低了铂类药物的肾毒性。总之，这项研究强调了 Pt-青蒿琥酯配合物作为抗肿瘤和抗疟药物的治疗潜力。
