Dicopper Complexes of p -Cresol-2,6-bis(amide-tether-dpa 4-X ) (X = MeO and Cl): Selective ROS Generation and Cytotoxicity Enhancement Controlled by Electronic and Hydrophobic Effects of the MeO and Cl Groups.

Two new p -cresol-2,6-bis(amide-tether-dpa 4-X ) ligands (HL 4-X , X = MeO and Cl) and their dicopper complexes [Cu 2 (μ-1,1-OAc)(μ-1,3-OAc)(L 4-MeO )]Y (Y = PF 6 1a , OAc 1b ) and [Cu 2 (μ-1,3-OAc) 2 (L 4-Cl )]Y (Y = ClO 4 2a , OAc 2b ) were synthesized. The electronic and hydrophobic effects of the MeO and Cl groups were examined compared with nonsubstituted complex [Cu 2 (μ-1,1-OAc)(μ-1,3-OAc)(L)] + ( 3 ). The electronic effects were found in crystal structures, spectroscopic characterization, and redox potentials of these complexes. 1b and 2b were reduced to Cu(I)Cu(I) with sodium ascorbate and reductively activated O 2 to produce H 2 O 2 and HO • . The H 2 O 2 release and HO • generation are promoted by the electronic effects. The hydrophobic effects increased the lipophilicity of 1b and 2b . Cellular ROS generation of 1b , 2b , and 3 was visualized by DCFH-DA. To examine the intracellular behavior, boron dipyrromethene (Bodipy)-modified complexes 4B and 5B corresponding to 1b and 2b were synthesized. These support that 1b and 2b are localized at the ER and Golgi apparatus. The cytotoxicity of 1b and 2b against various cell lines was examined by MTT assay. 1b and 2b were 7- and 41-fold more cytotoxic than 3 . 1b generated ROS selectively in cancer cell but 2b nonselectively in cancer and normal cells, causing cancer- and normal-cell-selective cytotoxicity, respectively.