Ditopic binuclear copper(II) complexes for DNA cleavage

Herein we present the synthesis of two ligands containing two di(2-picolyl)amine (DPA) units linked by either a 1,1′-(pyridine-2,6-diyl)bis(3-ethylurea) (L1) or a 1,1′-(1,3-phenylene)bis(3-ethylurea) (L2) spacer. The corresponding binuclear Cu II and Zn II complexes were prepared and isolated. The X-ray structures of the L1 ligand and the [Cu 2 L1Cl 2 ] 2+ complex evidence an unusual cis/trans conformation of one of the urea groups stabilized by an intramolecular hydrogen bond with the nitrogen atom of the pyridyl spacer. The Cu II complexes form rather strong ternary complexes with phosphorylated anions. The [Cu 2 L1] 4+ complex presents a rather high affinity for pyrophosphate (logK 11 = 8.19 at pH 7, 25 °C), while [Cu 2 L2] 4+ stands out because of its strong binding to AMP 2− (logK 11 = 9.3 at pH 7, 25 °C). The interaction of the Cu II complexes with deoxyribonucleic acid from calf thymus (ct-DNA) was monitored using circular dichroism (CD) and luminescence spectroscopies. These studies revealed a quite strong interaction of the complexes with ct-DNA (K b = (6.4 ± 0.7) × 10 3 for [Cu 2 L1] 4+ and K b = (6.3 ± 1.0) × 10 3 for [Cu 2 L2] 4+ ). Competition experiments carried out in the presence of methyl green and BAPPA (N 1 ,N 3 -Bis(4-amidinophenyl)propane-1,3-diamine) as major and minor groove competitors, respectively, confirm that the interaction of both complexes with DNA takes place through the minor groove, in agreement with docking studies. The [Cu 2 L2] 4+ complex is quite efficient in promoting the cleavage of the double-stranded pUC19 plasmid DNA, by favoring the conversion of the supercoiled form to the nicked form following a hydrolytic mechanism.