Dicopper Complexes of -Cresol-2,6-bis(amide-tether-dpa) (X = MeO and Cl): Selective ROS Generation and Cytotoxicity Enhancement Controlled by Electronic and Hydrophobic Effects of the MeO and Cl Groups.

Two new -cresol-2,6-bis(amide-tether-dpa) ligands (HL, X = MeO and Cl) and their dicopper complexes [Cu(μ-1,1-OAc)(μ-1,3-OAc)(L)]Y (Y = PF , OAc ) and [Cu(μ-1,3-OAc)(L)]Y (Y = ClO , OAc ) were synthesized. The electronic and hydrophobic effects of the MeO and Cl groups were examined compared with nonsubstituted complex [Cu(μ-1,1-OAc)(μ-1,3-OAc)(L)] (). The electronic effects were found in crystal structures, spectroscopic characterization, and redox potentials of these complexes. and were reduced to Cu(I)Cu(I) with sodium ascorbate and reductively activated O to produce HO and HO. The HO release and HO generation are promoted by the electronic effects. The hydrophobic effects increased the lipophilicity of and . Cellular ROS generation of , , and was visualized by DCFH-DA. To examine the intracellular behavior, boron dipyrromethene (Bodipy)-modified complexes and corresponding to and were synthesized. These support that and are localized at the ER and Golgi apparatus. The cytotoxicity of and against various cell lines was examined by MTT assay. and were 7- and 41-fold more cytotoxic than . generated ROS selectively in cancer cell but nonselectively in cancer and normal cells, causing cancer- and normal-cell-selective cytotoxicity, respectively.