A cyclometalated iridium(III) complex with 2-acetylpyridine-N(4)-ortho-chlorophenyl thiosemicarbazone: Potent...

The cyclometalated [Ir(CN)₂(H2Ac4oClPh)]Cl·2H₂O complex, hereafter named Ir(III) complex, was obtained from the reaction of dichlorotetrakis(2-(2-pyridinyl)phenyl)diiridium(III), [Ir₂(NC)₄Cl₂] (P1) with 2-acetylpyridine N(4)-ortho-chlorophenyl thiosemicarbazone (H2Ac4oClPh). The Ir(III) complex and H2Ac4oClPh exhibited cytotoxic effects against A549 lung and PC3 prostate cancer cells, with IC₅₀ values below 5 μM. Although the Ir(III) complex showed a higher IC₅₀ value against PC3 prostate cancer cells than H2Ac4oClPh, it exhibited a higher selectivity index (SI = IC_{50 L929}/IC_{50 PC3} L929: non-malignant fibroblast cells). The Ir(III) complex did not strongly inhibit thioredoxin reductase (TrxR) activity, suggesting that its mode of action does not involve TrxR inhibition. Hoechst 33342 staining revealed that A549 cells treated with the Ir(III) complex underwent nuclear fragmentation and chromatin condensation, indicating the occurrence of cell death. After 6 h treatment with Ir(III) complex, the iridium levels in A549 tumor cells were almost 75-fold higher than after treatment with the synthesis precursor P1, which probably could explain the potent cytotoxic effects of Ir(III) complex and the low activity of P1. The antibacterial activity of Ir(III) complex against Gram-positive Bacillus subtillis bacteria was comparable to that of ciprofloxacin used as a control. The results of the present work represent a significant contribution to the investigations on the pharmacological profile of iridium(III) complexes.