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
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DOI：
10.1016/j.ica.2004.10.027
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发表时间：
2005-03-30
影响因子：
2.8
通讯作者：
Haase, W
中科院分区：
文献类型：
--
作者：
Rossi, LM;Neves, A;Haase, W
不对称双核配体 N-(2-羟基苄基)-N,N',N'-三(2-吡啶基甲基)-1,3-二氨基丙-2-醇 (L = H(2)btppnol) 和相应的铜(II)络合物 [Cu-2(Hbtppnol)(mu-CH3COO)](ClO4)(2) (1) 最近在一份简短的通讯中部分报道了[Inorg。化学。通讯。 8（1999）334]。在本研究中，我们研究了复合物 I 促进磷酸二（2,4-二硝基苯基） (2,4-BDNPP) 中 P-O 磷酸二酯键水解以及基因组和质粒 DNA 分子裂解的能力。 1 与过量的二酯 2,4-BDNPP 在 pH 7.0 下反应，形成磷酸单酯配位的 [Cu-2(Hbtppnol)(mu-((NO2)(2)-C6H3)PO4)]ClO4 (3) 络合物，该络合物也通过 X 射线晶体学进行了表征。此外，磷酸4-硝基苯酯与配合物1反应得到的稳定的mu-磷酸配合物[Cu-2(Hbtppnol)(mu(NO2-C6H4)PO4)](ClO4)(2)也通过X射线晶体学进行了表征，表明1无法裂解单酯-磷酸键。研究了配合物 1 促进双(2,4-二硝基苯基)磷酸盐 (2,4-BDNPP) 水解的动力学作为 pH、催化剂浓度和底物浓度的函数。基于动力学和电位研究、氘同位素效应（k(H)/k(D)类似于1）和反应产物磷酸单酯配位[Cu-2(Hbtppnol)(mu-((NO2)(2)-C6H3)PO4)]ClO4 (3)络合物的X射线结构，我们证明了水/羟基 [Cu-2(II)(L)(OH2)(OH)]络合物是活性物质，反应通过形成三元络合物发生，其中一个 Cu-II 与底物结合，第二个铜中心具有末端结合的氢氧化物，在生理 pH 下攻击磷原子。相对于相同条件下未催化反应测量的速率增强因子，计算出类似于 100 的速率增强因子。在生理 pH 条件下，复合物 1 可能通过与 1 与 2,4-BDNPP 反应一致的水解机制有效促进双链基因组和质粒 DNA 的裂解。最后，研究了1对人小细胞肺癌细胞系（GLC4）及其顺铂耐药亚系（GLC4/CDDP）的细胞毒活性，并测定了IC50值。 (c) 2004 Elsevier B.V. 保留所有权利。
The unsymmetric dinucleating ligand N-(2-hydroxybenzyl)-N,N',N'-tris(2-pyridylmethyl)-1,3-diaminopropan-2-ol (L = H(2)btppnol) and the corresponding copper(II) complex [Cu-2(Hbtppnol)(mu-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 I 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 [Cu-2(Hbtppnol)(mu-((NO2)(2)-C6H3)PO4)]ClO4 (3) complex, which was also characterized by X-ray crystallography. In addition, the stable mu-phosphate complex [Cu-2(Hbtppnol)(mu(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 (k(H)/k(D)similar to 1) and the X-ray structure of the monoester phosphate coordinated [Cu-2(Hbtppnol)(mu-((NO2)(2)-C6H3)PO4)]ClO4 (3) complex as the product of the reaction, we demonstrated that the aquo/hydroxo [Cu-2(II)(L)(OH2)(OH)] 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 similar to 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. (c) 2004 Elsevier B.V. All rights reserved.