Artemisinin and its derivatives (ARTs) are being studied for their potential anti-tumor activity. Dimerization of artemisinin has been proposed as a promising means of enhancing drug efficacy. However, the sequential progression from monomers to dimers and trimers, retaining a consistent β-configuration, has not been previously investigated in terms of its effect on compound activity. To investigate the effect of various oligomeric forms on drug potency, we synthesized β-configuration-based ARTs, namely a monomer, dimer, and trimer, and rigorously characterized their structure. We evaluated the antitumor efficacy of these compounds against MCF-7 breast cancer cells. The artemisinin trimer 6a (β, β, β) exerted a stronger cytotoxic effects against MCF-7 breast cancer cells, with an IC₅₀ value of 0.09 ± 0.03 μM, than did the monomer (β) or dimer (β, β), which had IC₅₀ values of >50 and 3.14 ± 0.54 μM, respectively. This specific configuration induced alterations in nuclear morphology, inhibited colony formation, and facilitated cancer cell death. Mechanistic studies revealed that 6a (β, β, β) promoted apoptosis by modulating the Bax-caspase 3 signaling pathway and induced ferroptosis by regulating key signaling molecules, including GPX4. This study introduces an innovative methodology-a stepwise synthesis strategy progressing from monomers to dimers and trimers-to explore the relationship between oligomeric structure and drug activity. These findings provide novel insight into the architecture-activity relationship of ART derivatives, offering a foundation for advancing drug design and improving clinical applications.

2023-08-24·Journal of medicinal chemistry1区 · 医学

Facilitated Drug Repurposing with Artemisinin-Derived PROTACs: Unveiling PCLAF as a Therapeutic Target.

1区 · 医学

Article

作者: Zhao, Yong Long ; Yue, Ling Yun ; Chen, Lei ; Li, Yan ; Zhu, Ren Guang ; Gu, Zhi Cheng ; Zeng, Zi Wei ; Zhao, Qing Jie ; He, Bin ; Chen, Di ; Yan, Wan Li

Artemisinin, a prominent anti-malaria drug, is being investigated for its potential as a repurposed cancer treatment. However, its effectiveness in tumor cell lines remains limited, and its mechanism of action is unclear. To make more progress, the PROteolysis-TArgeting chimera (PROTAC) technique has been applied to design and synthesize novel artemisinin derivatives in this study. Among them, AD4, the most potent compound, exhibited an IC₅₀ value of 50.6 nM in RS4;11 cells, over 12-fold better than that of its parent compound, SM1044. This was supported by prolonged survival of RS4;11-transplanted NOD/SCID mice. Meanwhile, AD4 effectively degraded PCLAF in RS4;11 cells and thus activated the p21/Rb axis to exert antitumor activity by directly targeting PCLAF. The discovery of AD4 highlights the great potential of using PROTACs to improve the efficacy of natural products, identify therapeutic targets, and facilitate drug repurposing. This opens a promising avenue for transforming other natural products into effective therapies.

2023-06-01·Zhongguo shi yan xue ye xue za zhi

[Effect of a Novel Dihydroartemisinin Dimer Containing Nitrogen Atoms SM 1044 on Apoptosis of Human Leukemia Cell Line NB4-R1].

Article

作者: Zhao, Ling-Ling ; Cui, Wen ; Xue, Zheng ; Mi, Jian-Qing ; Li, Ying

题目新型含氮双氢青蒿素二聚体对人白血病细胞株NB4-R1细胞凋亡的影响.目的探讨新型水溶性含氮双氢青蒿素二聚体SM 1044对全反式维甲酸耐药急性早幼粒细胞白血病细胞株NB4-R1细胞凋亡的影响及其可能的机制。.方法流式细胞术检测SM 1044对细胞凋亡、线粒体跨膜电位以及细胞活性氧（ROS）水平的影响，Western blot检测SM 1044对MAPK（ERK、JNK）信号通路以及PML/RARα融合蛋白的影响和凋亡相关蛋白表达的变化。.结果SM 1044能够显著诱导NB4-R1细胞发生细胞凋亡以及线粒体跨膜电位丢失，同时能活化凋亡相关蛋白caspase-3、caspase-8、caspase-9以及抗多腺苷二磷酸核糖聚合酶；SM 1044可诱导NB4-R1细胞产生ROS；Western blot检测结果显示，SM 1044能够激活MAPK（ERK、JNK）信号通路的磷酸化，同时下调PML/RARα融合蛋白的表达。.结论SM 1044能够诱导全反式维甲酸耐药急性早幼粒细胞白血病细胞株NB4-R1细胞凋亡，其诱导凋亡可能与ROS/ERK以及ROS/JNK信号通路有关，此外，SM 1044也可通过下调PML/RARα融合蛋白诱导细胞凋亡。.

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床前	中国	贵州医科大学	2023-08-08
子宫内膜癌	临床前	中国	复旦大学	2019-10-29
子宫内膜癌	临床前	加拿大	University of British Columbia	2019-10-29