Mitochondrial-DNA-Targeted Ir III -Containing Metallohelices with Tunable Photodynamic Therapy Efficacy in Cancer Cells

• Published in: Angewandte Chemie International Edition 2020-04, Vol.59 (16), p.6420-6427
• Main Authors: Li, Xuezhao, Wu, Jinguo, Wang, Lei, He, Cheng, Chen, Liyong, Jiao, Yang, Duan, Chunying
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Binding Sites; Cell Line, Tumor; Coordination Complexes - chemistry; Coordination Complexes - metabolism; Coordination Complexes - pharmacology; Crystallography, X-Ray; DNA, Mitochondrial - chemistry; DNA, Mitochondrial - metabolism; Humans; Iridium - chemistry; Light; Microscopy, Confocal; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Conformation; Molecular Docking Simulation; Reactive Oxygen Species - metabolism; Stereoisomerism
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201915281

The development of DNA-targeted photodynamic therapy (PDT) agents for cancer treatment has drawn substantial attention. Herein, the design and synthesis of dinuclear Ir -containing luminescent metallohelices with tunable PDT efficacy that target mitochondrial DNA in cancer cells are reported. The metallohelices are fabricated using dynamic imine-coupling chemistry between aldehyde end-capped fac-Ir(ppy) handles and linear alkanediamine spacers, followed by reduction of the imine linkages. The length and odd-even character of the diamine alkyl linker determined the stereochemistry (helicates vs. mesocates). Compared to the helicates, the mesocates exhibit improved apoptosis-induction upon white-light irradiation. Molecular docking studies indicate that the mesocate with a proper length of diamine spacers shows stronger affinity for the minor groove of DNA. This study highlights the potential of DNA-targeting Ir -containing metallohelices as PDT agents.