Organoiridium Photosensitizers Induce Specific Oxidative Attack on Proteins within Cancer Cells

• Published in: Angewandte Chemie International Edition Vol. 56; no. 47; pp. 14898 - 14902
• Main Authors: Zhang, Pingyu, Chiu, Cookson K. C., Huang, Huaiyi, Lam, Yuko P. Y., Habtemariam, Abraha, Malcomson, Thomas, Paterson, Martin J., Clarkson, Guy J., O'Connor, Peter B., Chao, Hui, Sadler, Peter J.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 20.11.2017; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: A549 Cells; Absorption cross sections; Aldehyde reductase; bioinorganic; Cancer; cells; Chelating Agents - chemistry; Chelation; Communication; Communications; Crystallography; Crystallography, X-Ray; Cytotoxicity; Density Functional Theory; Glycolysis; Heat shock proteins; Histidine; Histidine - chemistry; Humans; Iridium; Iridium - chemistry; Iridium compounds; Irradiation; Ligands; Luminescence; Multicellular tumor spheroids; Neoplasm Proteins - chemistry; Neoplasm Proteins - metabolism; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; Phosphorescence; Photoactivation; Photochemical Processes; Photon absorption; photosensitizers; Photosensitizing Agents - pharmacology; Quinolines - chemistry; Spheroids; Spheroids, Cellular - drug effects; X-ray crystallography; bioinorganic; iridium; cancer; cells; photosensitizers
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201709082

Strongly luminescent iridium(III) complexes, [Ir(C,N)2(S,S)]+ (1) and [Ir(C,N)2(O,O)] (2), containing C,N (phenylquinoline), O,O (diketonate), or S,S (dithione) chelating ligands, have been characterized by X‐ray crystallography and DFT calculations. Their long phosphorescence lifetimes in living cancer cells give rise to high quantum yields for the generation of 1O2, with large 2‐photon absorption cross‐sections. 2 is nontoxic to cells, but potently cytotoxic to cancer cells upon brief irradiation with low doses of visible light, and potent at sub‐micromolar doses towards 3D multicellular tumor spheroids with 2‐photon red light. Photoactivation causes oxidative damage to specific histidine residues in the key proteins in aldose reductase and heat‐shock protein‐70 within living cancer cells. The oxidative stress induced by iridium photosensitizers during photoactivation can increase the levels of enzymes involved in the glycolytic pathway. In for a shock: A highly luminescent organoiridium complex generates 1O2 efficiently and oxidizes specific residues of heat‐shock protein‐70 and aldose reductase within cancer cells. The oxidative stress induced by iridium photosensitizers during photoactivation can increase the levels of the enzymes involved in the glycolytic pathway.