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Chem Sci. 2019 Jan 31;10(11):3315-3323. doi: 10.1039/c8sc04520h. eCollection 2019 Mar 21.

Inhibition of autophagic flux by cyclometalated iridium(iii) complexes through anion transportation.

Author information

1
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry , School of Chemistry , Sun Yat-Sen University , Guangzhou 510275 , P. R. China . Email: tancaip@mail.sysu.edu.cn ; Email: cesmzw@mail.sysu.edu.cn.
2
Guangdong Provincial Key Laboratory of New Drug Screening , School of Pharmaceutical Sciences , Southern Medical University , Guangzhou 510515 , P. R. China . Email: whchen@smu.edu.cn.

Abstract

Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H2biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H2biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents.

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