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Synthesis, structure and biological activity of a new and efficient Cd(II)–uracil derivative complex system for cleavage of DNA

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Abstract

The new complex formed by Cd(II) and the 1:2 Schiff-base-type ligand 2,6-bis[1-(4-amino-1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopyrimidin-5-yl)imino]ethylpyridine (DAPDAAU) has been chemically and structurally characterized by X-ray diffraction: the ion Cd(II) is surrounded by six nitrogen atoms from two DAPDAAU ligands which coordinates each one in a tridentate fashion through the pyridine ring (N1) and both azomethine nitrogen atoms (N5). The interaction of the Cd(II) complex (compound I) with calf-thymus DNA as observed by circular dichroism spectroscopy suggests the initial unwinding of the DNA double helix strongly depends on increasing incubation times and metal-to-nucleic acid molar ratios. Electrophoretic experiments indicate that the cadmium complex induces cleavage of the plasmid pBR322 DNA to give ulterior nicking and shortening of this molecule, as a result of the complex binding to DNA, resulting in the conclusion that compound I behaves as a chemical nuclease. Cytotoxic activity of the Cd(II) complex against selected different human cancer cell lines is specific and increases with increasing concentration of the metal compound; this fact indicates the potential antitumor character of the complex. When the culture medium is supplemented with compound I, a remarkable inhibition of the growing cell is observed, important cell degeneration appears before 48 h and abundant precipitates are formed that correspond to cell residues and denatured proteins.

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Abbreviations

CD:

Circular dichroism

CdL:

[Cd(DAPDAAU)2](ClO4)2·2.5H2O

DAAU:

5,6-Diamino-1,3-dimethyluracil

DAP:

2,6-Diacetylpyridine

DAPDAAU:

2,6-Bis[1-(4-amino-1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopyrimidin-5-yl)imino]ethylpyridine

DMSO:

Dimethyl sulfoxide

ESI:

Electrospray ionization

HPLC:

High-performance liquid chromatography

HMBC:

Heteronuclear multiple bond connectivity

MS:

Mass spectrometry

MTT:

3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazole

OC:

Open circular

SC:

Supercoiled

Tris:

Tris(hydroxymethyl)aminomethane

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Acknowledgements

The authors greatly appreciate financial support from MCYT, Spain (grants PPQ2000-0035-P4 and BQU2001-2455) and EC (COST Chemistry Projects D20/005 and D20/009).

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Authors and Affiliations

  1. Departamento de Química Orgánica e Inorgánica, Facultad de Ciencias Experimentales, Universidad de Jaén, 23071, Jaén, Spain

    Nuria A. Illán-Cabeza, Francisco Hueso-Ureña & Miguel N. Moreno-Carretero

  2. Departamento de Química Inorgánica, Laboratorio de Química Inorgánica Biológica, Facultad de Química, Universidad de Sevilla, 41071, Seville, Spain

    Rosario A. Vilaplana, Khalid Akdi, Sanae Kamah & Francisco González-Vílchez

  3. Laboratorio de Investigación Bioquímica, Universidad Autónoma de Madrid, HGUM Cantoblanco, 28049, Madrid, Spain

    Ysmael Alvarez

  4. Departamento de Química Inorgánica, Facultad de Ciencias, Universidad de Granada, 18041, Granada, Spain

    Miguel Quirós

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  1. Nuria A. Illán-Cabeza
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  2. Rosario A. Vilaplana
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  3. Ysmael Alvarez
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Correspondence to Francisco González-Vílchez.

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Illán-Cabeza, N.A., Vilaplana, R.A., Alvarez, Y. et al. Synthesis, structure and biological activity of a new and efficient Cd(II)–uracil derivative complex system for cleavage of DNA. J Biol Inorg Chem 10, 924–934 (2005). https://doi.org/10.1007/s00775-005-0045-x

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