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Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents

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Abstract

Three classes of kojic acid derivatives were synthesized and examined for their antiproliferative activity against HeLa cells. Both 8b and 11 co-treated with copper ion exhibited synergistic effect on the HeLa cell growth inhibition with GI50 values of 11.9 and 7.1 μM, respectively. Flow cytometric analysis of HeLa cells revealed that 11-Cu co-treatment induced the sub-G1 arrest in a dose-dependent manner, suggesting that the growth-inhibitory effect is attributed to DNA fragmentation. Moreover, western blot of HeLa cells cytosolic extracts displayed the cleavage of the 116-kDa protein poly(ADP-ribose) polymerase and activation of caspase-3 by the reduced level of the 32-kDa proenzyme, indicating that the caspase-dependent apoptotic pathway was involved. We further demonstrated that MAPK pathway regulators such as ERK and p38 were activated in response to 11-Cu co-treatment, suggesting that the intracellular oxidative stress was dramatically stimulated by the copper ion. Taken together, we have successfully synthesized kojic acid-derived copper-induced apoptotic agents.

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Acknowledgments

Financial support from the National Science Council of the Republic of China and Tamkang University to A. Y. Shaw is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Chemistry, Tamkang University, New Taipei City, 251, Taiwan

    Yu-Hua Chen

  2. Institute of Clinical Medicine, National Cheng Kung University, Tainan, 701, Taiwan

    Pei-Jung Lu

  3. Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA

    Christopher Hulme & Arthur Y. Shaw

  4. BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd, Oro Valley, AZ, 85737, USA

    Christopher Hulme & Arthur Y. Shaw

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  1. Yu-Hua Chen
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  2. Pei-Jung Lu
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  4. Arthur Y. Shaw
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Correspondence to Arthur Y. Shaw.

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Chen, YH., Lu, PJ., Hulme, C. et al. Synthesis of kojic acid-derived copper-chelating apoptosis inducing agents. Med Chem Res 22, 995–1003 (2013). https://doi.org/10.1007/s00044-012-0094-y

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  • DOI: https://doi.org/10.1007/s00044-012-0094-y

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