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.
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.
Ruiz
Rebeca
R
Departamento de Química, Universidad de Burgos, 09001, Burgos, Spain.
García
Begoña
B
Garcia-Tojal
Javier
J
Busto
Natalia
N
Ibeas
Saturnino
S
Leal
José M
JM
Martins
Célia
C
Gaspar
Jorge
J
Borrás
Joaquín
J
Gil-García
Rubén
R
González-Alvarez
Marta
M
D015097:3-Mercaptopropionic Acid / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D053960:DNA Breaks / Q000187:drug effects; D004229:Dithiothreitol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D009152:Mutagenicity Tests; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011067:Poly dA-dT / Q000235:genetics / Q000378:metabolism*; D011089:Polydeoxyribonucleotides / Q000235:genetics / Q000378:metabolism*; D013057:Spectrum Analysis; D013696:Temperature; D013882:Thiosemicarbazones / Q000737:chemistry*; D014783:Viscosity
D009942:Organometallic Compounds; D011089:Polydeoxyribonucleotides; D013882:Thiosemicarbazones; D011067:Poly dA-dT; C019530:poly(dC-dG); C013996:2-formylpyridine thiosemicarbazone; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; D015097:3-Mercaptopropionic Acid; D005978:Glutathione; D004229:Dithiothreitol