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

Sixteen novel mononuclear Cu-II, Co-II, Zn-II, and Ni-II complexes of the biologically active ligand clotrimazole (cloth) of the forms [M(clotri)(2)Cl-2]center dot nH(2)O (1-4), [M(clotri)(2)Br-2]center dot nH(2)O (5-7), [M(clotri)(3)Br-2] (8), [M(clotri)(3)NO3]NO3 center dot nH(2)O (9, 11), [M(clotri)(3)(NO3)(2)]center dot nH(2)O (10), and [M(clotri)(3)(OH2)(2)NO3]NO3 center dot nH(2)O (12) were synthesized and fully characterized. Dinuclear [Cu-2(clotri)(4)mu(2)-Cl-4]center dot 2H(2)O (1a) and [Cu-2(clotri)(4)mu(2)-Br-2]center dot 2H(2)O (5b) as well as tetranuclear [Cu-4(clotri)(4)mu(4)-Br-6 mu(4)-O] (5a) complexes were also isolated. Complexes 1-7,9, and 11 present a tetrahedral geometry; complex 8 exhibits a pentacoordinated structure; complexes la, 10 and 12 an octahedral geometry. X-ray crystal structures of [Cu(clotri)(2)Cl-2](1), [Cu(clotri)(2)(EtOH)Cl-2] (1.EtOH), [Zn(clotri)(2)Cl-2] (3), [Zn(clotri)(2)Br-2] (7), and (Cu-4(clotri)(4)mu(4)-Br-6 mu(4)-O] (5a) were obtained. Complexes 1-12 were tested for cytotoxic activity against the human carcinoma cell lines HeLa (cervix-uterine), PO (prostate), and HCT-15 (colon) displaying IC50 values <30 mu W. 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 Cu-II complexes 1 and 9. H-1 NMR studies of the Zn-II complexes showed that they can bind to nucleotides. (C) 2012 Elsevier Inc. All rights reserved.