Six artesunate (ART) conjugated ruthenium(II) complexes (Ru(II)-ART conjugates) with the formula [Ru(N^N)₂bpy(4-CH₃-4′-CH₂OART)](PF₆)₂ (Ru-ART-1-3) and [Ru(N^N)₂bpy(4-CH₂OART-4′-CH₂OART)](PF₆)₂ (Ru-ART-4–6) (N^N = 2,2′-bipyridine (bpy, in Ru-ART-1 and Ru-ART-4), 1,10-phenanthroline (phen, in Ru-ART-2 and Ru-ART-5) and 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru-ART-3 and Ru-ART-6)), were synthesized and characterized. Among them, Ru-ART-1-3 and Ru-ART-4-6 carry one and two ART moieties, respectively. Ru-ART-3 and Ru-ART-6 exhibit better cytotoxicity among six Ru(II)-ART conjugates. These two complexes can be effectively taken up by human cervical carcinoma (HeLa) cells. In addition, they selectively kill cancer cell lines while mildly affect normal cells. Mechanism studies have shown that HeLa cells treated with Ru-ART-3 and Ru-ART-6 show typical apoptotic characteristics (morphology changes, mitochondrial dysfunction, caspase cascade, etc.). On the other hand, the up regulation of Beclin-1 and conversion of LC3-I to LC3-II note the appearance of autophagy. As a result, Ru-ART-3 and Ru-ART-6 induce autophagy-dependent cell apoptosis via mitochondrial dysfunction and reactive oxygen species (ROS) accumulation.

Graphic abstract

中文翻译：

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钌(II)多吡啶配合物与青蒿琥酯的合成、表征及抗肿瘤机制研究

六种青蒿琥酯 (ART) 共轭钌 (II) 配合物 (Ru(II)-ART 共轭物)，分子式为 [Ru(N^N) ₂ bpy(4-CH ₃ -4' -CH ₂ OART)](PF ₆ ) ₂ ( Ru-ART-1-3 ) 和 [Ru(N^N) ₂ bpy(4-CH ₂ OART-4′-CH ₂ OART)](PF ₆ ) ₂ ( Ru-ART-4 – 6 ) ( N^N = 2,2'-联吡啶（bpy，在Ru-ART-1和Ru-ART-4 中）、1,10-菲咯啉（phen，在Ru-ART-2和Ru-ART-5 中）和 4 ,7-diphenyl-1,10-phenanthroline (DIP, in Ru-ART-3 andRu-ART-6 )) 被合成和表征。其中，Ru-ART-1-3和Ru-ART-4-6分别带有一个和两个 ART 部分。Ru-ART-3和Ru-ART-6在六种 Ru(II)-ART 偶联物中表现出更好的细胞毒性。这两种复合物可以被人宫颈癌（HeLa）细胞有效吸收。此外，它们选择性地杀死癌细胞系，同时轻微影响正常细胞。机理研究表明，用Ru-ART-3和Ru-ART-6处理的 HeLa 细胞表现出典型的凋亡特征（形态变化、线粒体功能障碍、caspase 级联等）。另一方面，Beclin-1 的上调和 LC3-I 向 LC3-II 的转化表明自噬的出现。因此，Ru-ART-3和Ru-ART-6通过线粒体功能障碍和活性氧 (ROS) 积累诱导自噬依赖性细胞凋亡。

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