Journal of the Korean Applied Science and Technology (한국응용과학기술학회지)

The Korean Society of Applied Science and Technology (한국응용과학기술학회)
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Cytochrome P-450 2A6 Inhibitor Based on the Indole Moiety

  • Lee, Soo (Department of Chemical Engineering, Changwon National University) ;
  • Lee, Hyang-Yeol (Department of Biotechnology, Korea National University of Transportation)
  • Received : 2012.08.21
  • Accepted : 2012.09.25
  • Published : 2012.09.30
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Abstract

The cytochrome P-450 enzymes (CYP 2A6) regulate many endogenous signaling molecules and drugs. Aryl alkynes such as 2-ethynylnaphthalene are important P450 inhibitors which have been extensively studied as medicines or as an effective chemical probes for profiling mouse liver microsomal P-450. Here we have synthesized indole-based novel P450 inhibitor, 5-ethynyl indole 3, and showed that it has successfully inhibited CYP 2A6 by chemical inhibition reaction. By using HPLC equipped with a photo diode array(PDA) detector, all of the peaks derived from the enzymatic reaction have been characterized.

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References

  1. K. Stark, and F. P. Guengerich, Characterization of Orphan Human Cytochromes 450, Drug Metab. Rev., 39, 627 (2007).
  2. R. Scott Obach, Qing-Yu Zhang, Deborah Dunbar, and Laurence S. Kaminsky, Metabolic Characterization of the Major Human Small Intestinal Cytochrome 450, Drug Metab. and Disp., 29 (3), 347 (2000).
  3. W. Zhang, T. Kilicarslan, R. F. Tyndale, and E. M. Sellers, Evalution of Methoxsalen, Tranylcypromine, and Tryptamine as Specific and Selective CYP2A6 Inhibitors in Vitro, Drug Metab. and Disp., 26(6), 897 (2001).
  4. P. W. Fan, C. Gu, S. A. Marsh, and J. C. Stevens, Mechanism-based Inactivation of Cytochrome 450, 2A6 by a Novel Terminal Acetylene Inhibitor, Drug Metab. and Disp., 31 (01), 28 (2003).
  5. M. Foroozesh, G. Primrose, Z. Guo, L. C. Bell, W. L. Alworth, and F. P. Guengerich, Aryl Acetylenes as Mechanism-based Inhibitors of Cytochrome 450-Dependent Monooxygenase Enzymes, Chem, Res. Toxicol., 10, 91 (1997).
  6. C. A. CaJacob, W. K. Chan, E. Shephard, and P. R. Ortiz de Monetellano, The Catalytic Site of Rat Hepatic Lauric Acid ${\omega}$-hydroxylase, J. Bio. Chem., 263 (35), 18640 (1988).
  7. J. K. Yano, M. H. Hsu, K. J. Griffin, C. D. Stout, E. F. Johnson, Structures of Human Microsomal Cytochrome P450 2A6 Complexed with Coumarin and Methoxsalen, Nat. Struc. Mol. Biol., 12, 822(2005).
  8. A. T. Wright, J. D. Song, and B. F. Cravatt, A Suite of Activity-based Probes for Human Cytochrome P450 Enzymes, J. Am. Chem. Soc. 131(30), 10692 (2009).
  9. A. T. Wright, and B. F. Cravatt, Chemical Proteomic Probes for Profiling Cytochrome P450 Activities and Drug Interactions in vivo, Chem. Biol., 14, 1043 (2007).
  10. A. E. Speers and B. F. Cravatt, Profiling Enzyme Activities in vivo using Click Chemistry Methods, Chem. Biol., 11, 535 (2004).
  11. S. E. Tully and B. F. Cravatt, Activity-based Probes that Target Functional Subclasses of Phospholipases in Proteomes, J. Am. Chem. Soc., 132, 3264 (2010).
  12. J. Gubbens, E. Ruijter, L.E.V. de Fays, J.M.A. Damen, B. de Kruijff, M. Slijper, D.T.S. Rijkers, R.M.J. Liskamp, and A.I.P.M. de Kroon, Photocrosslinking and Click Chemistry Enable the Specific Detection of Proteins Interacting with Phospholiquids at the Membrane Interface, Chem. Biol., 16 (2009).
  13. S. Lee and H.-Y. Lee, Studies of Vindoline Metabolism in Catharanthus Roseus Cell Cultures using Deuteriumlabeled Tabersonine. J. Kor. Oil Chem. Soc., 29(1), 71 (2012).
  14. H.-Y. Lee, N. Yerkes, and S. E. O'Connor, Aza-tryptamine Substrates in Monoterepene Indole Alkaloid Biosynthesis. Chem. Biol., 16, 1225 (2009).
  15. H.-Y. Lee, Analytical Characterization of Aza-indole Alkaloids in the Biosynthesis of Catharanthus Roseus, J. Kor. Oil Chem. Soc., 29(2), 248 (2012).
  16. C. Torborg, A. Zapf, and M. Beller, Palladium Catalysts for Highly Selective Sonogashira Reactions of Aryl and Heteroaryl Bromides, ChemSusChem, 1, 91 (2008).
  17. H. Henon, F. Anizon, R. M. Golsteyn, S. Leonce, R. Hofmann, B. Pfeiffer and M. Prudhomme, Synthesis and Biological Evaluation of New Dipyrrolo [3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, Substituted with Various Saturated and Unsaturated Side Chains Via Palladium Catalyzed Cross-coupling Reactions, Bioorg. Med. Chem., 14, 3825 (2006).
  18. W. Qu, S.-R. Choi, C. Hou, Z. Zhuang, S. Oya, W. Zhang, M.-P. Kung, R. Manchandra, D. M. Skovronsky, H. F. Kung, Synthesis and Evaluation of Indolinyl- and Indolylphenylacetylenes as Pet Imaging Agents for ${\beta}$-amyloid Plagues, Bioorg. Med. Chem. Lett., 18, 4823 (2008).