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

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• 作者：Soledad Betanzos-Lara ; Celedonio G¨®mez-Ruiz ; Lidia R. Barr¨®n-Sosa ; Isabel Gracia-Mora ; Marcos Flores-¨¢lamo ; Nor¨¢h Barba-Behrens
• 关键词：Coordination compound ; Clotrimazole ; Cytotoxicity ; Apoptosis ; Immunocytochemistry ; Nucleotides
• 刊名：Journal of Inorganic Biochemistry
• 出版年：2012
• 出版时间：September, 2012
• 年：2012
• 卷：114
• 期：Complete
• 页码：82-93
• 全文大小：1582 K

文摘

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)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)₄¦Ì²-Cl₄]¡¤2H₂O (1a) and [Cu₂(clotri)₄¦Ì²-Br₂]¡¤2H₂O (5b) as well as tetranuclear [Cu₄(clotri)₄¦Ì⁴-Br₆¦Ì⁴-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)₄¦Ì⁴-Br₆¦Ì⁴-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 ¦ÌM. 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. ¹H NMR studies of the Zn^II complexes showed that they can bind to nucleotides.