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
• 参考文献：1. H眉botter F. Beitr盲ge zur Kenntnis der chinesischen sowie der tibetisch-mongolischen Pharmakologie. Urban & Schwarzenberg; 1913.
  2. Kim, H, Ahn, BZ (1990) Antitumor effects of acetylshikonine and some synthesized naphthazarins on L1210 and S-180 systems. Yakhak Hoeji 34: pp. 262-266
  3. Miller, MG, Rodgers, A, Cohen, GM (1986) Mechanisms of toxicity of naphthoquinones to isolated hepatocytes. Biochem Pharmacol 35: pp. 1177-1184 CrossRef
  4. Moore, HW (1977) Bioactivation as a model for drug design bioreductive alkylation. Science 197: pp. 527-532 CrossRef
  5. Zhou, W, Zhang, X, Xiao, L, Ding, J, Liu, QH, Li, SS (2011) Semi-synthesis and antitumor activity of 6-isomers of 7, 8-O-dimethyl acylshikonin derivatives. Eur J Med Chem 46: pp. 3420-3427 CrossRef
  6. Papageorgiou, VP, Assimopoulou, AN, Couladouros, EA, Hepworth, D, Nicolaou, KC (1999) The chemistry and biology of alkannin, shikonin, and related naphthazarin natural products. Angew Chem Int Ed 38: pp. 270-301 CrossRef
  7. Wang, RB, Zhou, SS, Jiang, HDGL, Zheng, XG, Zhou, W, Li, SS (2012) An efficient multigram synthesis of alkannin and shikonin. Eur J Org Chem 2012: pp. 1373-1379 CrossRef
  8. Feng, LS, Lv, K, Liu, ML, Wang, S, Zhao, J, You, XF (2012) Synthesis and in vitro antibacterial activity of gemifloxacin derivatives containing a substituted benzyloxime moiety. Eur J Med Chem 55: pp. 125-136 CrossRef
  9. Zhou, W, Peng, Y, Li, SS (2010) Semi-synthesis and anti-tumor activity of 5,8-O-dimethyl acylshikonin derivatives. Eur J Med Chem 45: pp. 6005-6011 CrossRef
  10. Sistla, R, Tata, VSSK, Kashyap, YV, Chandrasekar, D, Diwan, PV (2005) Development and validation of a reversed-phase HPLC method for the determination of ezetimibe in pharmaceutical dosage forms. J Pharm Biomed Anal 15: pp. 517-522 CrossRef
  11. Messiano, GB, Santos, RAS, Ferreira, LDS, Sim玫es, RA, Jabor, VAP, Kato, MJ (2013) In vitro metabolism study of the promising anticancer agent the lignan (鈭?-grandisin. J Pharm Biomed Anal 72: pp. 240-244 CrossRef
  12. Newton, DJ, Wang, RW, Lu, AYH (1994) Cytochrome P450 inhibitors. Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 23: pp. 154-158
  13. Guidance for Industry: bioanalytical method validation. Center for Drug Evaluation and Research. United States Food and Drug Administration; 2001.
  14. Causon, R (1997) Validation of chromatographic methods in biomedical analysis viewpoint and discussion. J Chromatogr B Biomed Appl 689: pp. 175-180 CrossRef
  15. Ekins, S, Ring, BJ, Grace, J, McRobie-Belle, DJ, Wrighton, SA (2000) Present and future in vitro approaches for drug metabolism. J Pharmacol Toxicol Methods 44: pp. 313-324 CrossRef
  16. Fasinu, P, Bouic, PJ, Rosenkranz, B (2012) Liver-based in vitro technologies for drug biotransformation studies鈥揳 review. Curr Drug Metab 13: pp. 215-224 CrossRef
  17. Zhang DL, Zhu MS, Humphreys WG. Drug metabolism in drug design and development: basic concepts and practice. 2007;426. doi: 10.1002/9780470191699 .
  18. Kharasch, ED, Labroo, R (1992) Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology 77: pp. 1201-1207 CrossRef
  19. Shi, Q, Greenhaw, J, Salminen, WF (2013) Inhibition of cytochrome P450s enhances (+)-usnic acid cytotoxicity in primary cultured rat hepatocytes. J Appl Toxicol.
  20. Chiba, M, Hensleigh, M, Lin, JH (1997) Liver and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Major role of CYP3A. Biochem Pharmacol 53: pp. 1187-1195 CrossRef
  21. Li, H, Luo, S, Zhou, T (1999) Studies on in vitro metabolism of shikonin. Phytother Res 13: pp. 236-238 CrossRef
  22. Kumpulainen, H, M盲h枚nen, N, Laitinen, ML, Jaurakkaj盲rvi, M, Raunio, H, Juvonen, RO (2006) Evaluation of hydroxyimine as cytochrome P450-selective prodrug structure. J Med Chem 49: pp. 1207-1211 CrossRef
  23. Roberts, AB, Lamb, LC, Sporn, MB (1980) Metabolism of all-trans-retinoic acid in hamster liver microsomes: oxidation of 4-hydroxy- to 4-keto-retinoic acid. Arch Biochem Biophys 199: pp. 374-383 CrossRef
  
• 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.