Synthesis and pharmacological exploitation of clioquinol-derived copper-binding apoptosis inducers triggering reactive oxygen species generation and MAPK pathway activation

Abstract

In the present study, we carried out Mannich-type reaction to synthesize clioquinol-derived 7-methyl-arylsulfonylpiperazine analogs with improved growth-inhibitory effects. 11 bearing 5-nitro group on the quinoline ring exhibited 26-fold more potent than that of clioquinol against HeLa cells with a GI(50) value of 0.71 microM. In addition, 11 revealed synergistic effects on the growth inhibition of HeLa cells with GI(50) values of 0.65, 0.25, and 0.06 microM in the presence of 1, 10, and 50 microM copper, respectively. Consistent to the clioquinol-mediated apoptosis, mechanistic study indicates that 9- and 11-induced growth inhibition is attributed to caspase-dependent pathway. Detection of reactive oxygen species in response to clioquinol, 9 and 11 confirmed that ROS was dramatically stimulated in the presence of copper and partially abolished upon treatment of 1mM tempol. Further study indicated that 9- and 11-mediated induction of oxidative stress by ROS generation resulted in the activation MAPK pathway.