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Antitumor Activity of DMAKO-05, a Novel Shikonin Derivative, and Its Metabolism in Rat Liver Microsome

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Abstract

The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug.

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ACKNOWLEDGMENTS

This work was supported by the Shanghai Committee of Science and Technology, China (Grant No. 12431900602), and the State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China (CHEMR2012-B08). We also thank Vijaykanth Pagadala and Tim O’Leary for their critical reading of the manuscript.

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Authors and Affiliations

  1. School of Pharmacy, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China

    Xu Zhang, Ru-Bing Wang, Wen Zhou, Qing-Qing Meng & Shao-Shun Li

  2. Key Laboratory of Veterinary Drug Safety Evaluation and Residues Research, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China

    Sui Xiao

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  1. Xu Zhang
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  2. Ru-Bing Wang
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  3. Wen Zhou
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Correspondence to Wen Zhou or Shao-Shun Li.

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Xu Zhang and Ru-Bing Wang contributed equally to this work.

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Zhang, X., Wang, RB., Zhou, W. et al. Antitumor Activity of DMAKO-05, a Novel Shikonin Derivative, and Its Metabolism in Rat Liver Microsome. AAPS PharmSciTech 16, 259–266 (2015). https://doi.org/10.1208/s12249-014-0217-5

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