Triazolyl Ru^II, Rh^III Os^II, and Ir^III Complexes as Potential Anticancer Agents: Synthesis, Structure Elucidation, Cytotoxicity, and DNA Model Interaction Studies

Novel conjugated ruthenium(II), rhodium(III), and iridium(III) organometallic complexes of triazoles 1 and 2 synthesized and evaluated for anticancer activity against cervical (HeLa), kidney (HEK293), nonsmall lung cancer (A549), and leukemia (MT4) cancer cell lines are reported herein. The complexes are κ²-N,C coordinated and have the formula [ML(Ar)Cl] (where L is 1-benzyl-4-phenyl-1H-1,2,3-triazole for 1 and 1-benzyl-4-hydroxymethyl-1H-1,2,3-triazole for 2, Ar is p-cymene for Ru^II and Os^II and Cp∗ for Rh^III and Ir^III, and M is metal). NMR studies, including HMBC and NOESY, were employed to unambiguously elucidate their structures and provide their conformational information in solution. Single-crystal X-ray diffraction data have been used to establish the solid-state structures of selected complexes, which further confirm the structural elucidation by NMR. Dynamic NMR studies, such as differential transferred NOE, have been employed to distinguish between isomers 1a_I and 1a_II of ruthenium(II) complexes of triazole 1. The rhodium(III) (1b) and iridium(III) (1c) complexes exhibited good cytotoxic activities (CC₅₀ = 4-6 μM) comparable to that of the drug auranofin against lung cancer A549 cell lines (CC₅₀ = 4.69 μM). While triazole 1 based ruthenium(II) (1a) and osmium(II) (1d) complexes displayed modest anticancer activities against HeLa and HEK293 cell lines, the analogous rhodium(III) and iridium(III) complexes exhibited good potential (CC₅₀ = 9-54 μM versus auranofin (3-9 μM)) against these cancer cell lines. Insightful NMR studies on the interaction between the DNA model guanosine 5′-GMP and the complexes 1b,c reveal a possible mode of action of the aquated complexes involving carbenylation with DNA bases or purines through the triazolyl proton H-5. From the findings, these complexes could possibly confer their cytotoxic activities through intercalation with the DNA of pathological cells. Therefore, carbenylation of the triazolylrhodium(III) and iridium(III) complexes by DNA guanosine 5′-GMP is proposed as a novel mode of DNA intercalation of these complexes in cancer cells.