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

Hui Ling Chen, Chun Yi Chang, Hsun Tzu Lee, Hua Hsuan Lin, Pei Jung Lu, Chia Ning Yang, Chung Wai Shiau, Arthur Y. Shaw

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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 GI50 value of 0.71 μM. In addition, 11 revealed synergistic effects on the growth inhibition of HeLa cells with GI50 values of 0.65, 0.25, and 0.06 μM in the presence of 1, 10, and 50 μM 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 1 mM tempol. Further study indicated that 9- and 11-mediated induction of oxidative stress by ROS generation resulted in the activation MAPK pathway.

Original languageEnglish
Pages (from-to)7239-7247
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number20
DOIs
Publication statusPublished - 2009 Oct 15

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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