TY - JOUR
T1 - 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
AU - Ruiz, Rebeca
AU - García, Begoña
AU - Garcia-Tojal, Javier
AU - Busto, Natalia
AU - Ibeas, Saturnino
AU - Leal, José M.
AU - Martins, Célia
AU - Gaspar, Jorge
AU - Borrás, Joaquín
AU - Gil-García, Rubén
AU - González-Álvarez, Marta
PY - 2010/1/1
Y1 - 2010/1/1
N2 -
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.
AB -
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.
KW - Copper(II)
KW - Cytotoxicity
KW - DNA
KW - Pyridine-2-carbaldehyde thiosemicarbazone
KW - Thermodynamic properties
UR - http://www.scopus.com/inward/record.url?scp=77953359923&partnerID=8YFLogxK
U2 - 10.1007/s00775-009-0620-7
DO - 10.1007/s00775-009-0620-7
M3 - Article
C2 - 20087612
AN - SCOPUS:77953359923
SN - 0949-8257
VL - 15
SP - 515
EP - 532
JO - JBIC Journal of Biological Inorganic Chemistry
JF - JBIC Journal of Biological Inorganic Chemistry
IS - 4
ER -