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 [Cu₂L1Cl₂]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 [Cu₂L1]⁴⁺ complex presents a rather high affinity for pyrophosphate (logK₁₁ = 8.19 at pH 7, 25 °C), while [Cu₂L2]⁴⁺ stands out because of its strong binding to AMP^2- (logK₁₁ = 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) × 10³ for [Cu₂L1]⁴⁺ and K_b = (6.3 ± 1.0) × 10³ for [Cu₂L2]⁴⁺). Competition experiments carried out in the presence of methyl green and BAPPA (N¹,N³-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 [Cu₂L2]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.