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

Abstract Sixteen novel mononuclear Cu II , Co II , Zn II , and Ni II complexes of the biologically active ligand clotrimazole (clotri) of the forms [M(clotri) 2 Cl 2 ]· n H 2 O ( 1 – 4 ), [M(clotri) 2 Br 2 ]· n H 2 O ( 5 – 7 ), [M(clotri) 3 Br 2 ] ( 8 ), [M(clotri) 3 NO 3 ]NO 3 · n H 2 O ( 9 , 11 ), [M(clotri) 3 (NO 3 ) 2 ]· n H 2 O ( 10 ), and [M(clotri) 3 (OH 2 ) 2 NO 3 ]NO 3 · n H 2 O ( 12 ) were synthesized and fully characterized. Dinuclear [Cu 2 (clotri) 4 μ 2 –Cl 4 ]·2H 2 O ( 1a ) and [Cu 2 (clotri) 4 μ 2 –Br 2 ]·2H 2 O ( 5b ) as well as tetranuclear [Cu 4 (clotri) 4 μ 4 –Br 6 μ 4 –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) 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 μ 4 –Br 6 μ 4 –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 IC 50 values 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 . 1 H NMR studies of the Zn II complexes showed that they can bind to nucleotides.