Rhenium(I) Tricarbonyl Complexes of 1,10-Phenanthroline Derivatives with Unexpectedly High Cytotoxicity.

Eight rhenium(I) tricarbonyl aqua complexes with the general formula -[Re(CO)('-bid)(HO)][NO] (), where '-bid is (2,6-dimethoxypyridyl)imidazo[4,5-]1,10-phenanthroline (), (indole)imidazo[4,5-]1,10-phenanthroline (), (5-methoxyindole)-imidazo[4,5-]1,10-phenanthroline (), (biphenyl)imidazo[4,5-]1,10-phenanthroline (), (fluorene)imidazo[4,5-]1,10-phenanthroline (), (benzo[]thiophene)imidazo[4,5-]1,10-phenanthroline (), (5-bromothiazole)imidazo[4,5-]1,10-phenanthroline (), and (4,5-dimethylthiophene)imidazo[4,5-]1,10-phenanthroline (), were synthesized and characterized using H and C{H} NMR, FT-IR, UV/Vis absorption spectroscopy, and ESI-mass spectrometry, and their purity was confirmed by elemental analysis. The stability of the complexes in aqueous buffer solution (pH 7.4) was confirmed by UV/Vis spectroscopy. The cytotoxicity of the complexes () was then evaluated on prostate cancer cells (PC3), showing a low nanomolar to low micromolar cytotoxicity. Worthy of note, three of the Re(I) tricarbonyl complexes showed very low (IC = 30-50 nM) cytotoxic activity against PC3 cells and up to 26-fold selectivity over normal human retinal pigment epithelial-1 (RPE-1) cells. The cytotoxicity of both complexes and was lowered under hypoxic conditions in PC3 cells. However, the compounds were still 10 times more active than cisplatin in these conditions. Additional biological experiments were then performed on the most selective complexes (complexes and ). Cell fractioning experiments followed by ICP-MS studies revealed that and accumulate mostly in the mitochondria and nucleus, respectively. Despite the respective mitochondrial and nuclear localization of and , did not trigger the apoptosis pathways for cell killing, whereas can trigger apoptosis but not as a major pathway. Complex induced a paraptosis pathway for cell killing while did not induce any of our other tested pathways, namely, necrosis, paraptosis, and autophagy. Both complexes and were found to be involved in mitochondrial dysfunction and downregulated the ATP production of PC3 cells. To the best of our knowledge, this report presents some of the most cytotoxic Re(I) carbonyl complexes with exceptionally low nanomolar cytotoxic activity toward prostate cancer cells, demonstrating further the future viability of utilizing rhenium in the fight against cancer.