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

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• 作者：Xu Zhang (1)
  Ru-Bing Wang (1)
  Wen Zhou (1)
  Sui Xiao (2)
  Qing-Qing Meng (1)
  Shao-Shun Li (1)
  
  1. School of Pharmacy ; Shanghai Jiaotong University ; 800 Dongchuan Road ; Shanghai ; 200240 ; China
  2. Key Laboratory of Veterinary Drug Safety Evaluation and Residues Research ; Shanghai Veterinary Research Institute ; Chinese Academy of Agricultural Sciences ; 200241 ; Shanghai ; China
  
• 关键词：antitumor ; LC ; TOF ; MS/MS ; metabolism ; method validation ; rat hepatic microsomes ; shikonin oxime
• 刊名：AAPS PharmSciTech
• 出版年：2015
• 出版时间：April 2015
• 年：2015
• 卷：16
• 期：2
• 页码：259-266
• 全文大小：439 KB
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• 刊物主题：Pharmacology/Toxicology; Biotechnology; Biochemistry, general; Pharmacy;
• 出版者：Springer US
• ISSN：1530-9932

文摘

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.