Theophylline-based NHC–Ir(i) complexes bearing fluorinated benzyl groups as potential anticancer agents

Abstract

In this study, we present the synthesis, comprehensive characterization, and biological evaluation of a novel series of N-heterocyclic carbene iridium(I) (NHC–Ir(I)) complexes derived from theophylline. The structures of both the theophylline-based ligands and their corresponding metal complexes were elucidated using a combination of spectroscopic techniques, including multinuclear NMR, ATR-FTIR spectroscopy, mass spectrometry, and elemental analysis. We investigated the impact of fluorine substitution on the theophylline core, as well as the role of auxiliary ligands—cyclooctadiene (COD, complexes 3a–e) and carbonyl (CO, complexes 4a–e) on the coordination environment of the Ir(I) center. The cytotoxic activity of the synthesized complexes was evaluated against six human cancer cell lines, revealing insights into structure–activity relationships. While the free ligands exhibited no cytotoxicity, their NHC–Ir(I) complexes significantly enhanced anticancer activity. Among the tested complexes, those containing COD ligands (3a–e) demonstrated the highest cytotoxic potency. This effect was attributed to the challenges in oxidizing Ir(I) to its active Ir(III) species when CO ligands were present. Antioxidant assays and preliminary electrochemical studies confirmed that the formation of Ir(III) species play a crucial role in the observed cytotoxicity. Among all the complexes, 3c exhibited the most promising profile, showing potent activity against K-562, PC-3, and SKLU-1 cancer cells, with IC₅₀ values of 5.4 ± 0.2, 5.7 ± 1.0, and 8.5 ± 0.7 μM, respectively. Furthermore, complex 3c showed minimal toxicity toward healthy COS-7 cells and exhibited favorable physicochemical properties (log D = 2.87).