Cytotoxic copper(II), cobalt(II), zinc(II), and nickel(II) coordination compounds of clotrimazole

Sixteen novel mononuclear CuII, CoII, ZnII, and NiII complexes of the biologically active ligand clotrimazole (clotri) of the forms [M(clotri)2Cl2]·nH2O (1–4), [M(clotri)2Br2]·nH2O (5–7), [M(clotri)3Br2] (8), [M(clotri)3NO3]NO3·nH2O (9, 11), [M(clotri)3(NO3)2]·nH2O (10), and [M(clotri)3(OH2)2NO3]NO3·nH2O (12) were synthesized and fully characterized. Dinuclear [Cu2(clotri)4μ2–Cl4]·2H2O (1a) and [Cu2(clotri)4μ2–Br2]·2H2O (5b) as well as tetranuclear [Cu4(clotri)4μ4–Br6μ4–O] (5a) complexes were also isolated. Complexes 1–7, 9, and 11 present a tetrahedral geometry; complex 8 exhibits a pentacoordinated structure; complexes 1a, 10 and 12 an octahedral geometry. X-ray crystal structures of [Cu(clotri)2Cl2](1), [Cu(clotri)2(EtOH)Cl2](1·EtOH), [Zn(clotri)2Cl2] (3), [Zn(clotri)2Br2] (7), and [Cu4(clotri)4μ4–Br6μ4–O] (5a) were obtained. Complexes 1–12 were tested for cytotoxic activity against the human carcinoma cell lines HeLa (cervix–uterine), PC3 (prostate), and HCT-15 (colon) displaying IC50 values < 30 μM. Confocal microscopy and nuclear dying (DAPI) for complex 1 showed condensation of cromatin and nuclear membrane fragmentation. Immunocytochemical detection/expression of biomarkers suggests that complexes 1 and 9 induce cell death via apoptosis. TUNEL assay detected DNA fragmentation in HeLa cells, resulting from apoptotic signaling cascades induced by CuII complexes 1 and 9. 1H NMR studies of the ZnII complexes showed that they can bind to nucleotides.

Graphical abstractCuII, CoII, ZnII, and NiII complexes of clotrimazole are potent cytotoxic agents against human carcinoma cells. Confocal microscopy, immunocytochemical, and TUNEL assays suggest that CuII complexes induce cell death via apoptosis. Binding to 5′-GMP was observed for ZnII complexes in solution, suggesting that DNA might be a target.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► CuII, CoII, NiII and ZnII complexes of clotrimazole exhibit increased cytotoxicity. ► Imaging, immunocytochemical and TUNEL assays suggest apoptotic cell death. ► Binding to 5′-GMP was observed suggesting that DNA might be an important target.