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Published on: October 26, 2017
Coumarin-appended phosphorescent cyclometalated iridium(iii) complexes as mitochondria-targeted theranostic
Rui-Rong Ye1, Cai-Ping Tan1, Liang-Nian Ji1
1MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China. cesmzw@mail.sysu.edu.cn tancaip@mail.sysu.edu.cn.
Abstract:
Theranostic anticancer agents incorporating anticancer properties with capabilities for real-time treatment assessment are appealing candidates for chemotherapy. The design of mitochondria-targeted cytotoxic drugs represents a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, three coumarin-appended phosphorescent cyclometalated iridium(iii) complexes 1-3 have been explored as mitochondria-targeted theranostic anticancer agents. These complexes display rich photophysical properties, which facilitate the study of their intracellular fate. All three complexes can specifically target mitochondria and show much higher antiproliferative activities than cisplatin against various cancer cells including cisplatin-resistant cells. 1-3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphological changes in mitochondria. Mechanism studies show that 1-3 exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Genome-wide transcriptional and Connectivity Map analyses reveal that the cytotoxicity of complex 3 is associated with pathways involved in mitochondrial dysfunction and apoptosis.
Insights
New iridium(iii) complexes target mitochondria for cancer therapy, offering real-time monitoring and enhanced efficacy against resistant cells. These theranostic agents show promise for improved chemotherapy treatments.
Area of Science:
- Medicinal Chemistry
- Nanotechnology
- Biochemistry
Background:
- Theranostic agents combine therapeutic and diagnostic capabilities for enhanced cancer treatment.
- Mitochondria-targeted drugs offer selective tumor targeting and potential to overcome drug resistance.
- Iridium(iii) complexes are explored for their photophysical properties and anticancer potential.
Purpose of the Study:
- To design and evaluate novel mitochondria-targeted theranostic anticancer agents.
- To investigate the antiproliferative activity and intracellular fate of coumarin-appended iridium(iii) complexes.
- To elucidate the mechanism of action and assess theranostic capabilities.
Main Methods:
- Synthesis of three coumarin-appended phosphorescent cyclometalated iridium(iii) complexes (1-3).
- Evaluation of mitochondria targeting specificity and intracellular uptake in cancer cells (HeLa).
- Assessment of antiproliferative activity against various cancer cell lines, including cisplatin-resistant ones.
- Monitoring of mitochondrial morphological changes for theranostic assessment.
- Mechanism studies involving mitochondrial dysfunction and apoptosis pathway analysis using transcriptional and Connectivity Map analyses.
Main Results:
- Complexes 1-3 specifically target mitochondria in cancer cells.
- The complexes exhibit significantly higher antiproliferative activities than cisplatin, including against resistant cell lines.
- Efficient and rapid cellular uptake into HeLa cells was observed.
- Theranostic functions were demonstrated through simultaneous induction and monitoring of mitochondrial morphological changes.
- Mechanism studies indicated that complexes induce anticancer effects via mitochondrial dysfunction and apoptosis.
Conclusions:
- Coumarin-appended iridium(iii) complexes (1-3) are effective mitochondria-targeted theranostic anticancer agents.
- These complexes demonstrate superior efficacy compared to cisplatin and possess theranostic capabilities for real-time treatment monitoring.
- The observed cytotoxicity is linked to the induction of mitochondrial dysfunction and apoptosis, highlighting their potential in chemotherapy.
