کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1313212 | 975542 | 2005 | 16 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Synthesis, structure and properties of unsymmetrical μ-alkoxo-dicopper(II) complexes: biological relevance to phosphodiester and DNA cleavage and cytotoxic activity Synthesis, structure and properties of unsymmetrical μ-alkoxo-dicopper(II) complexes: biological relevance to phosphodiester and DNA cleavage and cytotoxic activity](/preview/png/1313212.png)
The unsymmetric dinucleating ligand N-(2-hydroxybenzyl)-N,N′,N′-tris(2-pyridylmethyl)-1,3-diaminopropan-2-ol (L = H2btppnol) and the corresponding copper(II) complex [Cu2(Hbtppnol)(μ-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–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)(μ-((NO2)2-C6H3)PO4)]ClO4 (3) complex, which was also characterized by X-ray crystallography. In addition, the stable μ-phosphate complex [Cu2(Hbtppnol)(μ-(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–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 (kH/kD ∼ 1) and the X-ray structure of the monoester phosphate coordinated [Cu2(Hbtppnol)(μ-((NO2)2-C6H3)PO4)]ClO4 (3) complex as the product of the reaction, we demonstrated that the aquo/hydroxo [Cu2II(L)(OH2)(OH)] complex is the active species and the reaction occurs through the formation of a ternary complex in which one CuII 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 ∼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.
Detailed kinetic studies, the deuterium isotope effect (kH/kD ∼ 1) and the X-ray structure of the monoesterphosphate (3) demonstrate that 1 hydrolyses bis(2,4-dinitrophenyl) phosphate (2,4-BDNPP) through intramolecular OH− attack and also effectively promotes the cleavage of double-stranded genomic and plasmid DNA, at physiological pH.Figure optionsDownload as PowerPoint slide
Journal: Inorganica Chimica Acta - Volume 358, Issue 6, 30 March 2005, Pages 1807–1822