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. 2015 Apr;16(2):259-66.
doi: 10.1208/s12249-014-0217-5. Epub 2014 Oct 2.

Antitumor activity of DMAKO-05, a novel shikonin derivative, and its metabolism in rat liver microsome

Xu Zhang  1 , Ru-Bing Wang, Wen Zhou, Sui Xiao, Qing-Qing Meng, Shao-Shun Li
Affiliations

Antitumor activity of DMAKO-05, a novel shikonin derivative, and its metabolism in rat liver microsome

Xu Zhang et al. AAPS PharmSciTech. 2015 Apr.

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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Figures

Fig. 1
Fig. 1
Chemical structure of DMAKO-05
Fig. 2
Fig. 2
Dose- and time-dependent inhibitory effect of DMAKO-05 (a) and 5-FU (b) on the cell growth of HCT 116 colorectal carcinoma cells using a MTT assay
Fig. 3
Fig. 3
HPLC chromatograms of eight metabolites and the parent compound DMAKO-05, extracted from rat liver microsome incubations at zero time (a) and 30 min (b)
Fig. 4
Fig. 4
A Michaelis-Menten kinetics plot and its magnified illustration of rat liver microsomes metabolism of DMAKO-05 at low substrate concentrations (a). Eadie-Hofstee analysis of DMAKO-05 (b)
Fig. 5
Fig. 5
Effects of various inhibitors on CYP450-mediated reactions in rat liver microsomes. (The Y axis means a percentage of the inhibitor-insensitive activity with the addition of different concentrations of inhibitors)
Fig. 6
Fig. 6
Metabolic products and the probable fragmentation patterns of DMAKO-05
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