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) (1,1) 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 = 8.19 at pH 7, 25 CC), while [Cu(2)L2](4+) stands out because of its strong binding to AMP(2-) (logK(11) = 9.3 at pH 7, 25 degrees 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 (Kb = (6.4 +/- 0.7) x 10(3) for [Cu(2)L1](4+) and K-b = (6.3 +/- 1.0) x 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.