Di-copper metallodrugs promote NCI-60 chemotherapy via singlet oxygen and superoxide production with tandem TA/TA and AT/AT oligonucleotide discrimination

In order to expand the current repertoire of cancer treatments and to help circumvent limitations associated with resistance, the identification of new metallodrugs with high potency and novel mechanisms of action is of significant importance. Here we present a class of di-copper(II) complex based on the synthetic chemical nuclease [Cu(Phen)(2)](+) (where Phen = 1,10-phenanthroline) that is selective against solid epithelial cancer cells from the National Cancer Institute's 60 human cell line panel (NCI-60). Two metallodrug leads are studied and in each case two [Cu(Phen)(2)](+) units are bridged by a dicarboxylate linker but the length and rigidity of the linkers differ distinctly. Both agents catalyze intracellular superoxide (O2(center dot-)) and singlet oxygen (O-1(2)) formation with radical species mediating oxidative damage within nuclear DNA in the form of double strand breaks and to the mitochondria in terms of membrane depolarization. The complexes are effective DNA binders and can discriminate AT/AT from TA/TA steps of duplex DNA through induction of distinctive Z-like DNA or by intercalative interactions.