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 (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.
Departamento de Química Inorgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, México, D.F. 04510, Mexico.
Soledad
S
Betanzos-Lara
Celedonio
C
Gómez-Ruiz
Lidia R
LR
Barrón-Sosa
Isabel
I
Gracia-Mora
Marcos
M
Flores-Álamo
Noráh
N
Barba-Behrens
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003022:Clotrimazole / Q000737:chemistry*; D003035:Cobalt / Q000737:chemistry*; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D053938:DNA Fragmentation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D003035:Cobalt; D003300:Copper; D009532:Nickel; D003022:Clotrimazole; D015032:Zinc