期刊
INORGANIC CHEMISTRY
卷 58, 期 22, 页码 15659-15670出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.inorgchem.9b02780
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资金
- Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India [EMR/2017/002324]
- Wellcome Trust India Alliance Fellowship [IA/I/16/1/502369]
- SERB, Department of Science and Technology, Government of India [ECR/2015/000220]
Ruthenium(II/III) complexes are predicted to be efficient alternatives to platinum drug-resistant cancers but have never been investigated for sequestration and efflux by Cu-ATPases (ATP7A or ATP7B) overexpressed in resistant cancer cells, although a major cause of platinum drug resistance is found to be sequestration of platinum chemotherapeutic agents by thiol donors glutathione (GSH) or the Cys-X-X-Cys (CXXC) motifs in the Cu-ATPases in cytosol. Here, we show for the first time that ATP7B efficiently sequesters ruthenium(II) eta(6)-p-cymene complexes. We present seven complexes, [Ru-II(eta(6)-p-cym)(L)X](PF6) (1-7; L = L1-L3, X = Cl, Br, and I), out of which two resists deactivation by the cellular thiol, glutathione (GSH). The results show that Ru-I coordination and a moderate steric factor increase resistance to GSH and the CXXC motif. Ru-II-I-coordinated 3 and 7 showed resistance to sequestration by ATP7B. 3 displays highest resistance against GSH and does not trigger ATP7B trafficking in the liver cancer cell line. It escapes ATP7B-mediated sequestration and triggers apoptosis. Thus, with a suitable bidentate ligand and iodido leaving group, Ru-II(eta(6)-p-cym) complexes may display strong kinetic inertness to inhibit the ATP7B detoxification pathway. Inductively coupled plasma mass spectrometry data show higher retention of 3 and 7 inside the cell with time compared to 4, supporting ATP7B-mediated sequestration.
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