Synthesis, structure and properties of unsymmetrical 脙脙脙脙-alkoxo-dicopper(II) complexes: biological relevance to phosphodiester and DNA cleavage and cytotoxic activity

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• 作者：Rossi ; Liane M. ; Neves ; Ademir ; Bortoluzzi ; Adailton J. ; H脙脙rner ; Rosmari ; Szpoganicz ; Bruno ; et. al.
• 关键词：Phosphodiester hydrolysis ; DNA cleavage ; Cytotoxic activity ; Unsymmetric Cu^IICu^II complexes
• 刊名：Inorganica Chimica Acta
• 出版年：2005
• 期刊代码：40_00201693
• 类别：ch
• 出版时间：March 30, 2005
• 卷：358
• 期：6
• 页码：1807-1822
• 文件大小：549 K

摘要

The unsymmetric dinucleating ligand N-(2-hydroxybenzyl)-N,N芒芒芒,N芒芒芒-tris(2-pyridylmethyl)-1,3-diaminopropan-2-ol (L=H₂btppnol) and the corresponding copper(II) complex [Cu₂(Hbtppnol)(芒芒-CH₃COO)](ClO₄)₂ (1) have been recently reported in part in a short communication [Inorg. Chem. Commum. 8 (1999) 334]. In this study, we investigated the ability of complex 1 to promote the hydrolysis of P芒芒芒O phosphate diester bonds in bis(2,4-dinitrophenyl) phosphate (2,4-BDNPP) and the cleavage of genomic and plasmid DNA molecules. Reaction of 1 with excess of the diester 2,4-BDNPP, at pH 7.0, results in the formation of the monoester phosphate coordinated [Cu₂(Hbtppnol)(芒芒-((NO₂)₂-C₆H₃)PO₄)]ClO₄ (3) complex, which was also characterized by X-ray crystallography. In addition, the stable 芒芒-phosphate complex [Cu₂(Hbtppnol)(芒芒-(NO₂-C₆H₄)PO₄)](ClO₄) (2) obtained from the reaction of 4-nitrophenyl phosphate with complex 1 was also characterized by X-ray crystallography, indicating that 1 is unable to cleave monoester芒芒芒phosphate bonds. The kinetics for the promotion of bis(2,4-dinitrophenyl) phosphate (2,4-BDNPP) hydrolysis by complex 1 was investigated as a function of pH, catalyst concentration and substrate concentration. On the basis of kinetic and potentiometric studies, the deuterium isotope effect (k^H/k^D芒芒芒1) and the X-ray structure of the monoester phosphate coordinated [Cu₂(Hbtppnol)(芒芒-((NO₂)₂-C₆H₃)PO₄)]ClO₄ (3) complex as the product of the reaction, we demonstrated that the aquo/hydroxo Formula Not Shown complex is the active species and the reaction occurs through the formation of a ternary complex in which one Cu^II binds the substrate and the second copper center has a terminal bound hydroxide to attack the phosphorus atom, at physiological pH. A rate enhancement factor of 芒芒芒100 was calculated relative to that measured for the uncatalyzed reaction under identical conditions. Complex 1 effectively promotes the cleavage of double-stranded genomic and plasmid DNA, at physiological pH, probably through a hydrolytic mechanism in agreement with that proposed for the reaction of 1 with 2,4-BDNPP. Finally, cytotoxic activity of 1 in a human small cell lung carcinoma cell line (GLC4) and its cisplatin resistant subline (GLC4/CDDP) was studied and the IC₅₀ values were determined.