Toward efficient Zn(II)-based artificial nucleases

被引:117
作者
Boseggia, E
Gatos, M
Lucatello, L
Mancin, F
Moro, S
Palumbo, M
Sissi, C
Tecilla, P
Tonellato, U
Zagotto, G
机构
[1] Univ Padua, Sez Padova, Dipartimento Sci Chim, I-35131 Padua, Italy
[2] Univ Padua, CNR, Ist Tecnol Membrane, I-35131 Padua, Italy
[3] Univ Padua, Dipartimento Sci Farmaceut, I-35131 Padua, Italy
[4] CNR, Ist Chim Inorgan & Superfici, I-35127 Padua, Italy
[5] Univ Trieste, Dipartimento Sci Chim, I-34127 Trieste, Italy
关键词
D O I
10.1021/ja039465q
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A series of cis-cis-triaminocyclohexane Zn(II) complex-anthraquinone intercalator conjugates, designed in such a way to allow their easy synthesis and modification, have been investigated as hydrolytic cleaving agents for plasmid DNA. The ligand structure comprises a triaminocyclohexane platform linked by means of alkyl spacers of different length (from C-4 to C-8) to the anthraquinone group which may intercalate the DNA. At a concentration of 5 muM, the complex of the derivative with a C-8 alkyl spacer induces the hydrolytic stand scission of supercoiled DNA with a rate of 4.6 x 10(-6) s(-1) at pH 7 and 37 degreesC. The conjugation of the metal complex with the anthraquinone group leads to a 15-fold increase of the cleavage efficiency when compared with the anthraquinone lacking Zn-triaminocyclohexane complex. The straightforward synthetic procedure employed, allowing a systematic change of the spacer length, made possible to gain more insight on the role of the intercalating group in determining the reactivity of the systems. Comparison of the reactivity of the different complexes shows a remarkable increase of the DNA cleaving efficiency with the length of the spacer. In the case of too-short spacers, the advantages due to the increased DNA affinity are canceled due to the incorrect positioning of the reactive group, thus leading to cleavage inhibition.
引用
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页码:4543 / 4549
页数:7
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