Iridium(III) polypyridine complexes with a disulfide linker as biological sensors and cytotoxic agents

The synthesis, characterization, and photophysical properties of two novel cyclometalated iridium(III) PEG complexes with a disulfide linkage [Ir(N^C)₂(bpy-SS-PEG)](PF₆) (bpy-SS-PEG = 4-(N-(2-((N-(2-(ω-methoxypoly(1-oxapropyl))ethyl)amino)cabonylethoxy)dithiolethoxy)carbonylamino)methyl-4′-methyl-2,2′-bipyridine; HN^C = methyl 2-phenyl-4-quinolinecarboxylate (pqe) (1a), 2-phenylquinoline (pq) (2a)), their PEG-free counterparts [Ir(N^C)₂(bpy-SS-py)](PF₆) (HN^C = pqe (1b), pq (2b)), their disulfide-free counterparts [Ir(N^C)₂(bpy-CONH-PEG)](PF₆) (bpy-CONH-PEG = 4-N-(2-(ω-methoxypoly-(1-oxapropyl))ethyl)aminocarbonyl)-4′-methyl-2,2′-bipyridine; (HN^C = pqe (1c), pq (2c)), and a bimetallic iridium(III)–rhenium(I) complex [Ir(pqe)₂(bpy-SS-py)Re(Me₄-phen)(CO)₃](PF₆)(CF₃SO₃) (Me₄-phen = 3,4,7,8-tetramethyl-1,10-phenathroline) (3) are reported. Upon irradiation, the complexes displayed intense green to red emission under ambient conditions. Complex 3 containing two communicating luminophores exhibited large spectral overlap and was found to have a theoretical FRET efficiency of 0.79. In the presence of GSH, the bimetallic disulfide-containing complex 3 would be cleaved which was followed by a 8-fold increase in emission intensity of the rhenium(I) moiety. The reaction was found to be specific toward Cys, GSH, and H₂S compared to other biothiols. Cell-based assays on complex 1a demonstrated that the addition of GSH to induce cleavage of the disulfide linkage would provide a more cytotoxic agent due to the release of the appended PEG pendant. Cellular localization studies by laser-scanning confocal microscopy in live HeLa cells indicated that complexes 1a–c exhibited punctate staining in the mitochondria.