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

J Inorg Biochem. 2012 Sep:114:82-93. doi: 10.1016/j.jinorgbio.2012.05.001. Epub 2012 May 9.

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)]·nH(2)O (1-4), [M(clotri)(2)Br(2)]·nH(2)O (5-7), [M(clotri)(3)Br(2)] (8), [M(clotri)(3)NO(3)]NO(3)·nH(2)O (9, 11), [M(clotri)(3)(NO(3))(2)]·nH(2)O (10), and [M(clotri)(3)(OH(2))(2)NO(3)]NO(3)·nH(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 <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 Cu(II) complexes 1 and 9. (1)H NMR studies of the Zn(II) complexes showed that they can bind to nucleotides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Clotrimazole / chemistry*
  • Cobalt / chemistry*
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / pharmacology
  • Copper / chemistry*
  • Crystallography, X-Ray
  • DNA Fragmentation / drug effects
  • Gene Expression / drug effects
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Microscopy, Confocal
  • Models, Molecular
  • Molecular Structure
  • Nickel / chemistry*
  • Zinc / chemistry*

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Ligands
  • Cobalt
  • Copper
  • Nickel
  • Clotrimazole
  • Zinc