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

This report presents Re(I)carbonyl complexes with exceptionallylow nanomolar cytotoxic activity toward prostate cancer cells, demonstratingfurther the future viability of utilizing rhenium in the fight againstcancer. Eight rhenium(I) tricarbonyl aqua complexes with thegeneral formula fac-[Re(CO)(3)(N,N & PRIME;-bid)(H2O)][NO3] (1-8), where N,N & PRIME;-bid is (2,6-dimethoxypyridyl)imidazo[4,5-f]1,10-phenanthroline (L1), (indole)imidazo[4,5-f]1,10-phenanthroline (L2), (5-methoxyindole)-imidazo[4,5-f]1,10-phenanthroline (L3), (biphenyl)imidazo[4,5-f]1,10-phenanthroline (L4), (fluorene)imidazo[4,5-f]1,10-phenanthroline (L5), (benzo[b]thiophene)imidazo[4,5-f]1,10-phenanthroline(L6), (5-bromothiazole)imidazo[4,5-f]1,10-phenanthroline (L7), and (4,5-dimethylthiophene)imidazo[4,5-f]1,10-phenanthroline (L8), were synthesizedand characterized using H-1 and C-13{H-1} NMR, FT-IR, UV/Vis absorption spectroscopy, and ESI-mass spectrometry,and their purity was confirmed by elemental analysis. The stabilityof the complexes in aqueous buffer solution (pH 7.4) was confirmedby UV/Vis spectroscopy. The cytotoxicity of the complexes (1-8) was then evaluated on prostate cancer cells (PC3), showing a lownanomolar to low micromolar in vitro cytotoxicity.Worthy of note, three of the Re(I) tricarbonyl complexes showed verylow (IC50 = 30-50 nM) cytotoxic activity againstPC3 cells and up to 26-fold selectivity over normal human retinalpigment epithelial-1 (RPE-1) cells. The cytotoxicity of both complexes 3 and 6 was lowered under hypoxic conditionsin PC3 cells. However, the compounds were still 10 times more activethan cisplatin in these conditions. Additional biological experimentswere then performed on the most selective complexes (complexes 3 and 6). Cell fractioning experiments followedby ICP-MS studies revealed that 3 and 6 accumulatemostly in the mitochondria and nucleus, respectively. Despite therespective mitochondrial and nuclear localization of 3 and 6, 3 did not trigger the apoptosispathways for cell killing, whereas 6 can trigger apoptosisbut not as a major pathway. Complex 3 induced a paraptosispathway for cell killing while 6 did not induce any ofour other tested pathways, namely, necrosis, paraptosis, and autophagy.Both complexes 3 and 6 were found to beinvolved in mitochondrial dysfunction and downregulated the ATP productionof PC3 cells. To the best of our knowledge, this report presents someof the most cytotoxic Re(I) carbonyl complexes with exceptionallylow nanomolar cytotoxic activity toward prostate cancer cells, demonstratingfurther the future viability of utilizing rhenium in the fight againstcancer.