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

文献类型： 外文期刊

第一作者： Zhang, Xu

作者： Zhang, Xu;Wang, Ru-Bing;Zhou, Wen;Meng, Qing-Qing;Li, Shao-Shun;Xiao, Sui

作者机构：

关键词： antitumor;LC-TOF-MS/MS;metabolism;method validation;rat hepatic microsomes;shikonin oxime

期刊名称：AAPS PHARMSCITECH （ 影响因子：3.246； 五年影响因子：3.473 ）

ISSN： 1530-9932

年卷期： 2015 年 16 卷 2 期

页码：

收录情况： SCI

摘要： 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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