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Synthesis, characterization and antitumor mechanism investigation of ruthenium(II) polypyridyl complexes with artesunate moiety

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Abstract

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

In this work, six artesunate (ART) conjugated ruthenium(II) complexes (Ru(II)-ART conjugates) have been synthesized and characterized. Among them, Ru-ART-3 and Ru-ART-6 exhibit better cytotoxicity. 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

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Acknowledgements

This work was supported by National Natural Science Foundation of China (21967014, 22007042), Applied Basic Research Projects of Yunnan Province (202001AT070036), the Innovative Team of Yunnan Province (No. 2019HC018), High-level Scientific Research Foundation for Talent Introduction of Kunming University of Science and Technology (KKKP201826008).

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  1. Bi-Chun Chen and Jun-Jian Lu have authors contributed equally.

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  1. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, People’s Republic of China

    Bi-Chun Chen, Jun-Jian Lu, Ning Jiang, Xiu-Rong Ma, Rong-Tao Li & Rui-Rong Ye

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  1. Bi-Chun Chen
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Chen, BC., Lu, JJ., Jiang, N. et al. Synthesis, characterization and antitumor mechanism investigation of ruthenium(II) polypyridyl complexes with artesunate moiety. J Biol Inorg Chem 26, 909–918 (2021). https://doi.org/10.1007/s00775-021-01901-8

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