NONRANDOM DOUBLE-STRAND CLEAVAGE OF DNA BY A MONOFUNCTIONAL METAL-COMPLEX - MECHANISTIC STUDIES

It has been demonstrated in our laboratory that the transition metal c omplex ibenzyl-5-methyl-3,7-diazanonanedioato)copper(III) (1) is capab le of mediating nonrandom double strand cleavage of plasmid DNA. Doubl e strand DNA cleavage is thought to be a biologically significant sour ce of cell lethality and is apparently an important mode of action for both the bleomycin and enediyne classes of antineoplastic agents. We present here the synthesis and characterization of 1 along with mechan istic studies of its DNA scission chemistry. Complex 1, upon reduction to the Cu(I) state in the presence of O-2, generates O-2(-) (HO2) and O-2(2-) (H2O2) which react to produce hydroxy radical through the Hab er-Weiss reaction. Hydroxy radical is known to abstract hydrogen from deoxyribose, leading to strand scission, release of base propenals, an d formation of abasic sites. The pseudo first order kinetics of single strand breakage (t(1/2) = 34 min), double strand breakage (t(1/2) = 2 1 min), and base propenal formation (t(1/2) = 100 min) have been measu red. Base propenal release is therefore kinetically distinct from stra nd scission, ruling out mechanisms which invoke concerted base propena l formation with strand scission.