title: Antitumor activity of DMAKO-05, a novel shikonin derivative, and its metabolism in rat liver microsome.
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.
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, 200240, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Ru-Bing
authors.initials: RB
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.forename: Sui
authors.initials: S
authors.lastname: Xiao
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Meng
authors.forename: Shao-Shun
authors.initials: SS
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D011355:Prodrugs; C016101:shikonin; D005472:Fluorouracil