Roles of DNA Target in Cancer Cell-Selective Cytotoxicity by Dicopper Complexes with DNA Target/Ligand Conjugates.

The DNA target/ligand conjugates (HL, X = P and M, = 1-3) were synthesized where various lengths of -CONH(CHCHO)CHCHNHCO- linkers with a 9-phenanthrenyl (P) or methyl (M) terminal as DNA targets replace the methyl group of 2,6-di(amide-tether cyclen)-cresol ligand (HL). DNA binding, DNA cleavage, cellular uptake, and cytotoxicity of Cu(μ-OH)(L) () are examined and compared with those of Cu(μ-OH)(L) () to clarify roles of DNA targets. Upon reaction of with HO, μ-1,1-OH complexes are formed for DNA cleavage. , , and are 22-, 11-, 3-fold more active for conversion of Form II to III in the cleavage of supercoiled plasmid DNA with HO than , where the short P-linker may fix a dicopper moiety within a small number of base pairs to facilitate DNA double-strand breaks (dsb). This enhances the proapoptotic activity of , , and , which are 30-, 12-, and 9.9-fold cytotoxic against HeLa cells than . DNA dsb and cytotoxicity are 44% correlated in but 5% in , suggesting specific DNA binding of P-linkers and nonspecific binding of M-linkers in biological cells. exert cancer cell-selective cytotoxicity against lung and pancreas cancer and normal cells where the short P-linker enhances the selectivity, but do not. Intracellular visualization, apoptosis assay, and caspase activity assay clarify mitochondrial apoptosis caused by . The highest cancer cell selectivity of may be enabled by the short P-linker promoting dsb of mitochondrial DNA with HO increased by mitochondrial dysfunction in cancer cells.