Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Acyl-CoA: Cholesterol Acyltransferase Inhibitors from llex macropoda

  • Im Kyung-Ran (Korea Research Institute of Bioscience and Biotechnology) ;
  • Jeong Tae-Sook (Korea Research Institute of Bioscience and Biotechnology) ;
  • Kwon Byoung-Mog (Korea Research Institute of Bioscience and Biotechnology) ;
  • Baek Nam-In (Graduate School of Biotechnology & Plant Metabolism Research Center, Kyunghee University) ;
  • Kim Sung-Hoon (Graduate School of East-West Medical Science, Kyunghee University) ;
  • Kim Dae-Keun (College of Pharmacy, Woosuk University)
  • Published : 2006.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Twigs from llex macropoda were extracted with MeOH, and the concentrated extracts were partitioned with $CH_2Cl_2$, EtOAc, n-BuOH, and $H_2O$. Repeated column chromatography of the $CH_2Cl_2$ fraction ultimately resulted in the isolation of two compounds, via activity-guided fractionation, using ACAT inhibitory activity measurements. According to the physico-chemical data, the chemical structures of these isolated compounds were identified as lupeol (1) and betulin (2). Compounds 1 and 2 were shown to inhibit the activity of hACAT-1 and hACAT-2 in a dose-dependent manner, and compounds 1 and 2 inhibited hACAT-1 with $IC_{50}$ values of 48 and $83{\mu}M$, respectively.

Keywords

References

  1. Ahmad, V. U. and Atta-ur-Rahman., Handbook of natural products data: pentacyclic triterpenoids. Vol. 2. Elsevier, New York, pp. 1038-1039, (1994)
  2. Anderson, R. A., Joyce, C., Davis, M., Reagan, J. W., Clark, M., Shelness, G. S., and Rudel, L. L., Identification of a form of acyl-CoA: cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J. Biol. Chem., 273, 26747- 26754 (1998) https://doi.org/10.1074/jbc.273.41.26747
  3. Brown, M. S., Dana, S. E., and Goldstein, J. L., Cholesterol ester formation in cultured human fibroblasts. J. Biol. Chem., 250, 4025-4027 (1975)
  4. Coses, S., Novak, S., Zheng, Y., Myers, H. M., Lear, S. R., Sande, E., Welch, C. B., Lusis, A. J., Spancer, T. A., Krouse, B. R., Erickson, S. K., Jr., and Farese, R. V. Jr., ACAT-2, a second mammalian acyl-CoA: cholesterol acyltransferase. J. Biol. Chem., 273, 26755-26764 (1998) https://doi.org/10.1074/jbc.273.41.26755
  5. Goodman, D. S., Deykin, D., and Shiratori, T., The formation of cholesterol esters with rat liver enzymes. J. Biol. Chem., 239, 1335-1345 (1964)
  6. Ito, K. and Lai, J., Studies on the constituents of Marsdenia formosana Masamune. I. Isolation of tirterpenoids and structure of marsformal. Yakugaku Zasshi, 98, 249-256 (1978) https://doi.org/10.1248/yakushi1947.98.3_249
  7. Jeong, T. S., Kim, J. R., Kim, K. S., Cho, K. H., Bae, K. H., and Lee, W. S., Inhibitory effects of multi-substituted benzylidenzethiazolidine- 2,4-diones on LDL oxidation. Bioorg. Med. Chem., 12, 4017-4023 (2004) https://doi.org/10.1016/j.bmc.2004.06.001
  8. Joyce, C. W., Sheiness, G. S., Davis, M. A., Lee, R. G., Skinner, K., Anderson, R. A., and Rudel, L. L., ACAT1 and ACAT2 membrane topology segregates a serine residue essential for activity to opposite sides of the endopasmic reticulum membrane. Mol. Biol. Cell, 11, 3675-3687 (2000) https://doi.org/10.1091/mbc.11.11.3675
  9. Kim, D. H., Jung, S. J., Chung, I-S., Lee, Y-Y., Kim, D. K., Kim, S., H., Kwon, B-M., Jeong, T-S., Park, M-H., Seoung, N-S., and Baek, N-I., Ergosterol peroxide from flowers of Erigeron annuus L. as an anti-atherosclerosis agent. Arch. Pharm. Res., 28, 541-545 (2005) https://doi.org/10.1007/BF02977755
  10. Kim, Y. K., Tomoda, H., and Nishida, H., Pyripyropenes, novel inhibitors of acyl-CoA: Cholesterol acyltransferase produced by Aspergillus fumigatus. J. Antibiot., 47, 154-162 (1994) https://doi.org/10.7164/antibiotics.47.154
  11. Lee, C. H., Jeong, T. S., Choi, Y. K., Hyun, B. W., Oh, G. T., Kim, E. H., Kim. J. R., Han, J. I., and Bok, S. H., Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP- 1 in high cholesterol-fed rabbits. Biochem. Biophys. Res. Commun., 284, 681-688 (2001) https://doi.org/10.1006/bbrc.2001.5001
  12. Leon, C., Hill, J. S., and Wasan, K. M., Potential role of acylcoenzyme A: cholesterol transferase (ACAT) inhibitors as hypolipidemic and antiatherosclerosis drugs. Pharm Res., 10, 1578-1588 (2005)
  13. Patra, A., Chaudhuri, S. K., and Panda, S. K., Betulin-3-caffeate from Quercus suber. $^{13}C-NMR$ spectra of some lupenes. J. Nat. Prod., 51, 217-220 (1988) https://doi.org/10.1021/np50056a004
  14. Roth, B. D., Blankley, J., and Hoefle, M. L., Inhibitors of acyl- CoA:cholesterol acyltransferase. 1. Identification and structureactivity relationships of a novel series of fatty acid anillide hypocholesterolemic agents. J. Med. Chem., 35, 1609-1617 (1992) https://doi.org/10.1021/jm00087a016
  15. Rudel, L. l., Lee, R. G., and Cockman, T. L., Acyl coenzyme A: cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis. Curr. Opin. Lipidol., 12, 121-127 (2001) https://doi.org/10.1097/00041433-200104000-00005
  16. Siddiqui, S., Hafeez, F., Begum, S., and Siddiqui, B. S., Oleanderol, a new pentacyclic triterpene from the leaves of Nerium oleander. J. Nat. Prod., 51, 229-233 (1988) https://doi.org/10.1021/np50056a006