Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 22, Issue 23, Pages 7800-7809Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201505160
Keywords
antitumor agents; ligands; lipophilicity; phosphorescence; rhenium
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Funding
- National Natural Science Foundation of China [21572282, 21231007, 21571196]
- State High-Tech Development Program (863 Program) [2012AA020305]
- Ministry of Education of China [IRT1298]
- National Basic Research Program of China (973 Program) [2015CB856301]
- Guangdong Natural Science Foundation [2015A030306023]
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Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1-Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase-independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase-independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes.
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