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

摘要

The dicopper(II) complex [Cu_2(R'SSR)_2(SO_4)_2] (1),where R'SSR is a Schiff base,has been prepared from the reaction of CuSO_4-5H_2O with the Schiffbase N,N',1,1'-dithiobis(ethylenesalicylaldimine) (H_2RSSR) 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 eta~3,mu_2-binding mode.The Cu ...Cu distance is 4.562(2) A with each copper having a square pyramidal (4 + 1) CuNO_4 coordination geometry.The monoanionic Schiff base R~tSSR has a pendant cationic amine -SCH_2CH_2NH_3~+ group which is presumably formed from the hydrolysis of one imine bond of H_2RSSR.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(SO_4)] (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 approx 3 (K_(app) = 5.4 x 10~5 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.