Synthetic analogue approach for the functional domains of copper(II) bleomycins and its DNA cleavage activity

Abstract

The dicopper(II) complex [Cu₂(R'SSR)₂(SO₄)₂] (1), where R'SSR is a Schiff base, has been prepared from the reaction of CuSO₄·5H₂O with the Schiff base N,N'-1,1'-dithiobis(ethylenesalicylaldimine) (H₂RSSR) and structurally characterized by X-ray crystallography. The crystal structure of 1 shows two {Cu(R'SSR)}²⁺ units linked by two sulfate ligands each showing a η³,μ₂-binding mode. The Cu···Cu distance is 4.562(2) Å with each copper having a square pyramidal (4 + 1) CuNO₄ coordination geometry. The monoanionic Schiff base R'SSR has a pendant cationic amine -SCH₂CH₂NH³⁺ group which is presumably formed from the hydrolysis of one imine bond of H₂RSSR. Complex 1 models the N- and C-terminus domains of bleomycins. The metal centers in 1 are essentially magnetically non-interacting giving a -2J value of 3 cm⁻¹ with the singlet as the ground state. Using complex 1 as a precursor, ternary copper(II) complexes [Cu(R'SSR)B(SO₄)] (2-4) are prepared, characterized and their DNA binding and cleavage properties studied (B: kanamycin A, 2; 2,2'-bipyridine, 3; 1,10-phenanthroline, 4). IR spectral data suggest a square pyramidal (4 + 1) geometry for the one-electron paramagnetic ternary complexes with the sulfate bound to copper. The complexes are non-conducting in DMF but show conductivity in aqueous medium due to dissociation of the sulfate ligand. They bind to calf thymus DNA in the minor groove giving the relative order: 4 > 2 > 1~3 (K_app=5.4 × 10⁵ M^-1 for 4). The precursor complex 1 does not show any apparent chemical nuclease activity when treated with supercoiled (SC) DNA in the presence of 3-mercaptopropionic acid (MPA). The kanamycin A and phen adducts as such or generated under in situ reaction conditions using 1 and the ligand display efficient chemical nuclease activity in the presence of MPA, while the bpy species shows poor cleavage activity. The ternary kanamycin A complex presents the first synthetic model for three functional domains of bleomycins.