Biological assays and noncovalent interactions of pyridine-2-carbaldehyde thiosemicarbazonecopper(II) drugs with [poly(dA-dT)] 2 , [poly(dG-dC)] 2 , and calf thymus DNA

Rebeca Ruiz, Begoña García, Javier Garcia-Tojal, Natalia Busto, Saturnino Ibeas, José M. Leal, Célia Martins, Jorge Gaspar, Joaquín Borrás, Rubén Gil-García, Marta González-Álvarez

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29 Citations (Scopus)

Abstract

The interaction of the Cu(II) drugs CuL(NO 3 ) and CuL'(NO 3 ) (HL is pyridine-2-carbaldehyde thiosemicarbazone and HL' is pyridine-2-carbaldehyde 4N-methylthiosemicarbazone, in water named [CuL] + and [CuL'] + ) with [poly(dA-dT)] 2 , [poly(dG-dC)] 2 , and calf thymus (CT) DNA has been probed in aqueous solution at pH 6.0, 1 = 0.1 M, and T = 25 °C by absorbance, fluorescence, circular dichroism, and viscosity measurements. The results reveal that these drugs act as groove binders with [poly(dA-dT)] 2 , with a site size n = 6-7, whereas they act as external binders with [poly(dG-dC)] 2 and/or CT-DNA, thus establishing overall electrostatic interaction with n = 1. The binding constants with [CuL'] + were slightly larger than with [CuL]+. The title compounds display some cleavage activity in the presence of thiols, bringing about the rupture of the DNA strands by the reactive oxygen species formed by reoxidation of Cu(I) to Cu(II); this feature was not observed in the absence of thiols. Mutagenic assays performed both in the presence and in the absence of S9 mix, probed by the Ames test on TA 98, TA 100, and TA 102, were negative. Weak genotoxic activity was detected for [CuL] + and [CuL'] + , with a significative dose-response effect for [CuL'] + , which was shown to be more cytotoxic in the Ames test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assays. Methylation of the terminal NH 2 group enhances the antiproliferative activity of the pyridine-2carbaldehyde thiosemicarbazones.

Original languageEnglish
Pages (from-to)515-532
Number of pages18
JournalJournal of Biological Inorganic Chemistry
Volume15
Issue number4
DOIs
Publication statusPublished - 1 Jan 2010

Keywords

  • Copper(II)
  • Cytotoxicity
  • DNA
  • Pyridine-2-carbaldehyde thiosemicarbazone
  • Thermodynamic properties

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