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, I = 0.1 M, and T = 25 degrees 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-2-carbaldehyde thiosemicarbazones.

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This work provides structural evidence for different desulfurization processes in aqueous solutions of [CuL] + derivatives (HL = pyridine-2-carbaldehyde thiosemicarbazone). Structural resolution has been achieved for the [{CuL(SH)} 2 ] (1), [CuLCl] 2 [Cu(pic) 2 ] (pic À = picolinato, pyridine-2-carboxilato) (2) and [Cu(HL)(NCS)](NO 3 ) (4) compounds, together with a derivative of 4 with formula [Cu(HL)(NCS)][Cu(HL)-(NCS) 0.72 (NO 3 ) 0.28 ](NO 3 ) 2 (5), whose HS À , pic À and NCS À ligands come from thiosemicarbazone breakage.The behaviour of the [CuL] + species in basic aqueous solutions or water under reflux has been compared with that exhibited by iron(III), cobalt(III), zinc(II) and lead(II) derivatives of the same thiosemicarbazone ligand. [Cu(L 0 )] + species (HL 0 = pyridine-2-carbaldehyde N4-methylthiosemicarbazone) have also been analyzed by infrared spectroscopy or mass spectrometry under the same experimental conditions. In addition, preparative methods for a rational synthesis of the serendipitously obtained compounds are proposed. In this way, the crystal structure of [CuL(pic)]Á3H 2 O (3) has been elucidated too. The partial desulfurization of coordinated thiosemicarbazones could lead to a reinterpretation of their biological activity with consequences for the search for possible therapeutic uses.