Chemical synthesis and characterization of epicatechin glucuronides and sulfates: Bioanalytical standards for epicatechin metabolite identification

Journal of Natural Products

Volumn 76, Issue 2, 2013, Pages 157-169

  Zhang, Mingbao ^a   Jagdmann, G Erik ^a   Zandt, Michael Van ^a   Sheeler, Ryan ^a   Beckett, Paul ^a   Schroeter, Hagen ^b  

^a Institutes for Pharmaceutical Discovery   (United States)

^b MARS Symbioscience   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3' O METHYLEPICATECHIN; 4' O BETA DEXTRO GLUCURONIDE; 4' O METHYLEPICATECHIN; 5 O BETA DEXTRO GLUCURONIDE; 7 O BETA DEXTRO GLUCURONIDE; DRUG METABOLITE; EPICATECHIN; EPICATECHIN 3' O BETA DEXTRO GLUCURONIDE; GLUCURONIDE; SULFATE; UNCLASSIFIED DRUG; 3'-O-METHYLEPICATECHIN; CATECHIN; DRUG DERIVATIVE; EPICATECHIN GLUCURONIDE; EPICATECHIN-GLUCURONIDE;

AQUEOUS SOLUTION; ARTICLE; DRUG GLUCURONIDATION; DRUG SULFATION; DRUG SYNTHESIS; ENVIRONMENTAL TEMPERATURE; HETERONUCLEAR MULTIPLE BOND CORRELATION; METHYLATION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; STRUCTURE ACTIVITY RELATION; CHEMICAL STRUCTURE; CHEMISTRY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; NUCLEAR MAGNETIC RESONANCE; SYNTHESIS;

CATECHIN; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; GLUCURONIDES; HUMANS; MOLECULAR STRUCTURE; NUCLEAR MAGNETIC RESONANCE, BIOMOLECULAR; SULFURIC ACID ESTERS;

MLCS; MLOWN;

EID: 84876710990     PISSN: 01633864     EISSN: 15206025     Source Type: Journal    
DOI: 10.1021/np300568m     Document Type: Article

References (43)

1. In this paper, the common names epicatechin and catechin designate the(2R, 3R)-and(2R, 3S)-epimers, respectively.
2. Porter, L. J. In The Flavonoids, Advances in Research since 1986; Harborne, J. B., Ed.; Chapman & Hall: Landon, 1994; pp 23-56.
3. Ellinger, S.; Reusch, A.; Stehle, P.; Helfrich, H. P. Am. J. Clin. Nutr. 2012, 95, 1365-1377.
4. Hooper, L.; Kay, C.; Abdelhamid, A.; Kroon, P. A.; Cohn, J. S.; Rimm, E. B.; Cassidy, A. Am. J. Clin. Nutr. 2012, 95, 740-751.
5. Schroeter, H.; Heiss, C.; Spencer, J. P.; Keen, C. L.; Lupton, J. R.; Schmitz, H. H. Mol. Aspects Med. 2010, 31, 546-557.
6. Van Praag, H.; Lucero, M. J.; Yeo, G. W.; Stecker, K.; Heivand, N.; Zhao, C.; Yip, E.; Afanador, M.; Schroeter, H.; Hammerstone, J.; Gage, F. H. J. Neurosci. 2007, 27, 5869-5878.
7. Heiss, C.; Jahn, S.; Taylor, M.; Real, W. M.; Angeli, F. S.; Wong, M. L.; Amabile, N.; Prasad, M.; Rassaf, T.; Ottaviani, J. I.; Mihardja, S.; Keen, C. L.; Springer, M. L.; Boyle, A.; Grossman, W.; Glantz, S. A.; Schroeter, H.; Yeghiazarians, Y. J. Am. Coll. Cardiol. 2010, 56, 218-224.
8. Curtis, P. J.; Sampson, M.; Potter, J.; Dhatariya, K.; Kroon, P. A.; Cassidy, A. Diabetes Care 2012, 35, 226-232.
9. Schroeter, H.; Heiss, C.; Balzer, J.; Kleinbongard, P.; Keen, C. L.; Hollenberg, N. K.; Sies, H.; Kwik-Uribe, C.; Schmitz, H. H.; Kelm, M. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 1024-1029.
10. Mink, P. J.; Scrafford, C. G.; Barraj, L. M.; Harnack, L.; Hong, C. P.; Nettleton, J. A.; Jacobs, D. R., Jr. Am. J. Clin. Nutr. 2007, 85, 895-909.
11. Ottovani, J. I.; Kwik-Uribe, C.; Keen, C. L.; Schroeter, H. Am. J. Clin. Nutr. 2012, 95, 851-858.
12. Ottaviani, J. I.; Momma, T. Y.; Heiss, C.; Kwik-Uribe, C.; Schroeter, H.; Keen, C. L. Free Radical Biol. Med. 2011, 50, 237-244.
13. Natsume, M.; Osakabe, N.; Yasuda, A.; Osawa, T.; Terao, J. J. Clin. Biochem. Nutr. 2008, 42, 50-53.
14. Ottovani, J. I.; Momma, T. Y; Kuhnle, G. K.; Keen, C. L.; Schroeter, H. Free Radical Biol. Med. 2012, 52, 1403-1412.
15. Actis-Goretta, L.; Leveques, A.; Giuffrida, F.; Michailidis, F. R.; Viton, F.; Barron, D.; Duenas-Paton, M.; Gonzalez-Manzano, S.; Santos-Buelga, C.; Williamson, G.; Dionisi, F. Free Radical Biol. Med. 2012, 53, 787-95.
16. Li, C.; Meng, X.; Winnik, B.; Lee, M. J.; Lu, H.; Sheng, S.; Buckley, B.; Yang, C. S. Chem. Res. Toxicol. 2001, 14, 702-707.
17. Meng, X.; Sang, S.; Zhu, N.; Lu, H.; Sheng, S.; Lee, M. J.; Ho, C. T.; Yang, C. S. Chem. Res. Toxicol. 2002, 15, 1042-1050.
18. Piskula, M. K.; Terao, J. J. Nutr. 1998, 128, 1172-1178.
19. Spencer, J. P.; Chowrimootoo, G.; Choudhury, R.; Debnam, E. S.; Srai, S. K.; Rice-Evans, C. FEBS Lett. 1999, 458, 224-230.
20. Kuhnle, G.; Spencer, J. P.; Schroeter, H.; Shenoy, B.; Debnam, E. S.; Srai, S. K.; Rice-Evans, C.; Hahn, U. Biochem. Biophys. Res. Commun. 2000, 277, 507-512.
21. Donovan, J. L.; Crespy, V.; Manach, C.; Morand, C.; Besson, C.; Scalbert, A.; Remesy, C. J. Nutr. 2001, 131, 1753-1757.
22. Spencer, J. P.; Schroeter, H.; Kuhnle, G.; Srai, S. K.; Tyrrell, R. M.; Hahn, U.; Rice-Evans, C. Biochem. J. 2001, 354, 493-500.
23. Harada, M.; Kan, Y.; Naoki, H.; Fukui, Y.; Kageyama, N.; Nakai, M.; Miki, W.; Kiso, Y. Biosci. Biotechnol. Biochem. 1999, 63, 973-977.
24. Natsume, M.; Osakabe, N.; Oyama, M.; Sasaki, M.; Baba, S.; Nakamura, Y.; Osawa, T.; Terao, J. Free Radical Biol. Med. 2003, 34, 840-849.
25. Blount, J. W.; Ferruzzi, M.; Raftery, D.; Pasinetti, G. M.; Dixon, R. A. Biochem. Biophys. Res. Commun. 2012, 417, 457-461.
26. Gonzalez-Manzano, S.; Gonzalez-Paramas, A.; Santos-Buelga, C.; Duenas, M. J. Agric. Food Chem. 2009, 57, 1231-1238.
27. Duenas, M.; Gonzalez-Manzano, S.; Surco-Laos, F.; Gonzalez-Paramas, A.; Santos-Buelga, C. J. Agric. Food Chem. 2012, 60, 3592-3598.
28. The O-methylation of epicatechin and catechin primarily occurs at 3-OElig;-and 4-OElig;-OH via the action of catechol-O-methyltransferase, and only one OH group is methylated, limiting the total number of epicatechin glucuronides/sulfates that could be formed to 10 each(4 nonmethylated and 6 methylated forms). For references on enzymology of methylation of epicatechin and catechin, see:(a) Kuhnle, G.; Spencer, J. P.; Schroeter, H.; Shenoy, B.; Debnam, E. S.; Srai, S. K.; Rice-Evans, C.; Hahn, U. Biochem. Biophys. Res. Commun. 2000, 277, 507.
29. Lu H., Meng X., Yang C. S. Drug. Metab. Dispos. 2003, 31, 572-579.
30. During the preparation of this article, a paper describing the synthesis of four B-ring conjugates using a different synthetic approach has appeared: Romanov-Michailidis, F.; Viton, F.; Fumeaus, R.; Leveques, A.; Actis-Coretta, L.; Rein, M.; Williamson, G.; Barron, D. Org. Lett. 2012, 14, 3902-3905.
31. Mull, E. S.; Van Zandt, M.; Golebiowski, A.; Beckett, P.; Sharma, P. K.; Schroeter, H. Tetrahedron Lett. 2012, 53, 1501-1503.
32. Zhang, M.; Jagdmann, G. E., Jr.; Van Zandt, M.; Beckett, P.; Schroeter, H. Tetrahedron: Asymmetry, submitted.
33. Geissman, T. A. The Chemistry of Flavonoid Compounds; MacMillan: New York, 1962; p 446.
34. Pearson, A. G.; Kiefel, M. J.; Ferro, V.; Von Itzstein, M. Carbohydr. Res. 2005, 340, 2077-2085.
35. Needs, P. W.; Kroon, P. A. Tetrahedron 2006, 62, 6862-6868.
36. In one instance, adding BF3•OEt2 neat to the reaction resulted in significant C-2 epimerization of the epicatechin core to form the corresponding ent-catechin epimer. After removal of the acetyl, methyl, and benzyl protecting groups, the product was isolated as a mixture of ent-catechin-5-O-â-D- glucuronide(3G-OElig;) and epicatechin-5-O-â-Dglucuronide(3G) in a ratio of 2.5:1 as determined by HPLC. The two products were separated by preparative reversed-phase HPLC.
37. Characterization data of 3-OElig;-O-methyl-ent-catechin-4-OElig;-O- â-Dglucuronide(5G-OElig;): 1H NMR(acetone-d6 with 10% D2O, 400 MHz) ä 7.13(1H, d, J = 8.2 Hz, H-5-OElig;), 7.08(1H, s, H-2-OElig;), 6.96(1H, d, J = 8.3 Hz, H-6-OElig;), 6.01(1H, s, H-6), 5.86(1H, s, H-8), 5.08(1H, d, J = 7.0 Hz, H-1-), 4.58(1H, d, J = 8.3 Hz, H-2), 4.06-3.93(2H, m, H-5-, H-3), 3.84(3H, s, OCH3), 3.70-3.62(1H, m, H-3-), 3.62-3.53(2H, m, H-4-, H-2-), 2.93(1H, dd, J = 16.1, 5.7 Hz, H-4a), 2.49(1H, dd, J = 15.9, 9.0 Hz, H-4b); 13C NMR(acetone-d6 with 10% D2O, 100 MHz) ä 157.5, 157.1, 156.4, 149.7, 146.8, 135, 121.1, 116.5, 112.6, 101.8, 100.4, 96.2, 95.1, 82.3, 76.5, 73.9, 72.3, 68.1, 56.4, 29.0; LC/MS(negative mode) m/z 479 [M -H]-.
38. Abd El-Razek, M. H. Asian J. Chem. 2007, 19, 4867-4872.
39. Shen, C.-C.; Chang, Y.-S.; Ho, L.-K. Phytochemistry 1993, 34, 843-845.
40. Kiehlmann, E.; Lehto, N.; Cherniwchan, D. Can. J. Chem. 1988, 66, 2431-2439.
41. Liu, Y.; Lien, I.-F.; Ruttgaizer, S.; Dove, P.; Taylor, S. D. Org. Lett. 2004, 6, 209-212.
42. Ragan, M. A. Can. J. Chem. 1978, 56, 2681-2685.
43. LC/MS of these samples revealed no new molecular ions, suggesting that the new peaks were likely from the corresponding entcatechin sulfates formed as a result of the 4-OElig;-OH-induced C-2 epimerization during storage(see ref 32).