Synthesis, structure and properties of unsymmetrical μ-alkoxo-dicopper(II) complexes: biological relevance to phosphodiester and DNA cleavage and cytotoxic activity
Detailed kinetic studies, the deuterium isotope effect ( k H/ k D ∼ 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 ge...
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| Published in: | Inorganica Chimica Acta Vol. 358; no. 6; pp. 1807 - 1822 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Elsevier B.V
30-03-2005
|
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Detailed kinetic studies, the deuterium isotope effect (
k
H/
k
D
∼
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.
The unsymmetric dinucleating ligand
N-(2-hydroxybenzyl)-
N,
N′,
N′-tris(2-pyridylmethyl)-1,3-diaminopropan-2-ol (L
=
H
2btppnol) and the corresponding copper(II) complex [Cu
2(Hbtppnol)(μ-CH
3COO)](ClO
4)
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 [Cu
2(Hbtppnol)(μ-((NO
2)
2-C
6H
3)PO
4)]ClO
4 (
3) complex, which was also characterized by X-ray crystallography. In addition, the stable μ-phosphate complex [Cu
2(Hbtppnol)(μ-(NO
2-C
6H
4)PO
4)](ClO
4) (
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
∼
1) and the X-ray structure of the monoester phosphate coordinated [Cu
2(Hbtppnol)(μ-((NO
2)
2-C
6H
3)PO
4)]ClO
4 (
3) complex as the product of the reaction, we demonstrated that the aquo/hydroxo
[
Cu
2
II
(
L
)
(
OH
2
)
(
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 ∼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 IC
50 values were determined. |
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| ISSN: | 0020-1693 1873-3255 |
| DOI: | 10.1016/j.ica.2004.10.027 |