한국산학기술학회논문지 (Journal of the Korea Academia-Industrial cooperation Society)

  • 제12권11호
  • /
  • Pages.4940-4950
  • /
  • 2011
  • /
  • 1975-4701(pISSN)
  • /
  • 2288-4688(eISSN)
한국산학기술학회 (The Korea Academia-Industrial cooperation Society)
권호 표지
DOI QR코드

DOI QR Code

trans-(3R,5S)-Atorvastatin Ca의 합성 및 Rat에서 고지방식이로 유도된 고지혈증 치료효과

Synthesis of trans-(3R,5S)-Atorvastatin Ca and Curative Effect on Hyperlipidemia Induced by a High-Fat Diet in Rats

  • 최원식 (순천향대학교 생명공학과) ;
  • 남석우 (순천향대학교 생명공학과) ;
  • 이경락 (순천향대학교 생명공학과)
  • Choi, Won-Sik (Department of Biotechnology, Soonchunhyang University) ;
  • Nam, Seok-Woo (Department of Biotechnology, Soonchunhyang University) ;
  • Lee, Gyung-Rak (Department of Biotechnology, Soonchunhyang University)
  • 투고 : 2011.09.22
  • 심사 : 2011.11.10
  • 발행 : 2011.11.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

고지혈증 치료제인 cis-(3R,5R)-atorvastatin Ca (1)은 4개의 입체이성질체가 있으며, 각각의 이성질체들을 선택적으로 제조한다는 것은 매우 어려운 일이다. 본 연구에서는 입체이성질체 중의 하나인 trans-(3R,5S)-atorvastatin Ca (7)을 초산에서 3,5-diketo atorvastatin ester (3)를 $Me_4NHB(OAc)_3$을 사용하여 환원시켜 cis-(3R,5R) (4)과 trans-(3R,5S)-atorvastatin ester (5)를 각각 1.5%와 98.5%의 비율로 입체선택적으로 제조할 수 있었다. 또한, 고지혈증 치료제인 cis-(3R,5R)-atorvastatin Ca (1)과 그의 입체이성질체인 trans-(3R,5S)-atorvastatin Ca (7)을 쥐에서 고지방식이에 의해 유발된 고지혈증의 치료효과에 대하여 알아보았고, 이러한 연구의 수행을 위해 2010년 1월에 실험을 실시하였다. 그 결과, 화합물 1과 7의 total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c)과 triglyceride (TG)는 각각 $93.0{\pm}0.5$, $43.5{\pm}0.8$, $40.4{\pm}1.4$, $45.6{\pm}0.9\;mg/d{\ell}$와 $110.0{\pm}0.7$, $33.3{\pm}0.6$, $65.8{\pm}1.9$, $54.8{\pm}1.2\;mg/d{\ell}$를 atherogenic index (AI)와 cardiac risk factor (CRF)는 $1.14{\pm}0.05$ $2.14{\pm}0.05$와 $2.31{\pm}0.06$, $3.31{\pm}0.06$을 나타냈으며 aspartate aminotransferase (AST)와 alanine aminotransferase (ALT)는 $51.9{\pm}4.6$, $16.0{\pm}2.1\;IU/{\ell}$와 $75.8{\pm}4.4$, $35.1{\pm}9.7\;IU/{\ell}$로 두 화합물 모두 고지혈증에 대한 치료효과를 나타내었으나, 화합물 1이 우수한 치료효과가 있는 반면 화합물 7은 치료효과가 낮은 것을 확인하였다. 이러한 결과들로 입체선택적 이성질체의 합성에 대한 새로운 방법을 제시하고, 향후 시판되고 있는 의약품들의 입체이성질체에 대한 임상적 활용이 가능할 것으로 사료된다.

cis-(3R,5R)-Atorvastatin Ca (1) used for hyperlipidemia have four stereomers. However, It is very difficult to prepare stereoselective stereomers. In this paper, the reduction of 3,5-diketo atorvastatin ester (3) was performed using $Me_4NHB(OAc)_3$ in acetic acid as a reductant and showed excellent stereoselectivity in the double reduction of 3,5-diketo atorvastatin ester (3). As a result, reduction of compound 3 by $Me_4NHB(OAc)_3$ was purely obtained with cis-(3R,5R)-atorvastatin ester (4) of 1.5% and trans-(3R,5S)-atorvastatin ester (5) of 98.5%. Also, cis-(3R,5R)-atorvastatin Ca (1) and trans-(3R,5S)-atorvastatin Ca (7) were used to determine efficacy in the treatment of liver damage and hyperlipidemia induced by a high-fat diet in rats and to study the performance of the January 2010 experient was conducted. As a result, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), and triglyceride (TG) levels of compound 1 and 7 groups were $93.0{\pm}0.5$, $43.5{\pm}0.8$, $40.4{\pm}1.4$, $45.6{\pm}0.9\;mg/d{\ell}$ and $110.0{\pm}0.7$, $33.3{\pm}0.6$, $65.8{\pm}1.9$, $54.8{\pm}1.2\;mg/d{\ell}$, respectively. Atherogenic index (AI) and cardiac risk factor (CRF) in compound 1 and 7 were $1.14{\pm}0.05$, $2.14{\pm}0.05$ and $2.31{\pm}0.06$, $3.31{\pm}0.06$, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were $51.9{\pm}4.6$, $16.0{\pm}2.1\;IU/{\ell}$ and $75.8{\pm}4.4$, $35.1{\pm}9.7\;IU/{\ell}$. Taken together, while compound 1 treat against high-fat diet-induced hyperlipidemia by attenuating hepatic lipid depots and reducing oxidative stress, compound 7 group had a low curative effect on hyperlipidemia induced by a high-fat diet in rats. These findings suggest that new method about synthesis of stereoselective stereomers and indicate that it may consider using in a clinical trial.

키워드

참고문헌

  1. H. J. Lee, J. R. Do, J. H. Kwon and H. K. Kim, "Physiological activities of extracts from different parts of Cudrania tricuspidata", J. Korean Soc. Food Sci. Nutr., 40, pp. 942-948, 2011. https://doi.org/10.3746/jkfn.2011.40.7.942
  2. G. M. R. Tombo and D. Bellus, "Chiralitaet und Pflanzenschuetz, Angew", Chem., 103, pp. 1219- 1241, 1991.
  3. E. S. Choi, "A structure model development on the cardiovascular disease risk factors among the male manufacturing workers", J. Korean. Acad. Community Health Nurs., 17, pp. 153-165, 2006.
  4. E. H. Lee, S. J. Tahk, J. H. Shin, Y. W. Lee and R. Song, "Development and a psychometric evaluation of cardiovascular disease-specific quality of life scale for koreans", J. Korean. Acad. Nurs., 37, pp. 313-323, 2007. https://doi.org/10.4040/jkan.2007.37.3.313
  5. A. Endo, "Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase", J. Med. Chem., 28, pp. 401, 1985. https://doi.org/10.1021/jm00382a001
  6. T. Hiyama, G. B. Reddy, T. Minami and T. Hanamoto, "Stereoselective reduction of β,δ-diketo ester. A novel strategy for the synthesis of artificial HMG-CoA reductase inhibitors", Bull. Chem. Soc. Jpn., 68, pp. 350-363, 1995. https://doi.org/10.1246/bcsj.68.350
  7. L. Czako, A. Szabolcs, A. Vajda, S. Csati, V. Venglovecz, Z. Rakonczay Jr., P. Hegyi, L. Tiszlavicz, T. Csont, A. Posa, A. Berko, C. Varga, S. V. Ilona, I. Boros and J. Lonovics, "Hyperlipidemia induced by a cholesterol-rich diet aggravates necrotizing pancreatitis in rats", Eur. J. Pharmacol., 572, pp. 74-81, 2007. https://doi.org/10.1016/j.ejphar.2007.05.064
  8. A. Endo, M. Kuroda and K. Tanzawa, "ML-236A, ML-236B, AND ML-236C, New inhibitors of cholesterogenesis produced by penicillium citrinum", J. Antibiot., 29, pp. 1346-1348, 1976. https://doi.org/10.7164/antibiotics.29.1346
  9. B. D. Roth, D. R. Sliskovic and B. K. Trivedi, "Treatment of Hypercholesterolemia", Annu. Rep. Med. Chem., 24, pp. 147-156, 1989. https://doi.org/10.1016/S0065-7743(08)60538-2
  10. J. S. Kim, M. S. Kim, H. J. Park, S. J Jin, S. Lee and S. J. Hwang, "Physicochemical properties and oral bioavailability of amorphous atorvastatin hemicalcium using spray-drying and SAS process", Int. J. Pharmac., 359, pp. 211-219, 2008. https://doi.org/10.1016/j.ijpharm.2008.04.006
  11. W. Richmond, "Use of cholesterol oxidase for assay of total and free choresterol in serum by continuous flow analysis", Clin. Chem., 22, pp. 1579-1588, 1976.
  12. M. W. Mcgowan, J. D. Artiss and D. R. Strandbergh, "A peroxidase-coupled method for the colorimetric determination of serum triglyceride", Clin. Chem., 29, pp. 538-542, 1983.
  13. A. Noma, K. N. Nakayama, M. Kota and H. Okabe, "Simultaneous determination of serum cholesterol in high and low density lipoprotein with use of heparin, $Ca^{2+}$ and an anion exchange resin", Clin. Chem., 24, pp. 1504-1580, 1978.
  14. W. T. Friedwald, R. L. Levy and D. S. Fredrickson, "Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge", Clin. Chem., 18, pp. 499-502, 1972.
  15. O. Haglund, R. Loustarinen, R. Wallin, I. Wibell and T. Salden, "The effect of fish oil on triglycerides, cholesterol, fibrinogen and malondialdehyde in humans supplemented with vitamin", Eur. J. Nutr., 121, pp. 165-172, 1991.
  16. S. Reitman and S. Frankel, "A colorimetric method for the determination of serum glutamic oxaloacetic determination and glutamic pyruvic transaminase", Am. J. Clin. Pathol., 28, pp. 56-63, 1957. https://doi.org/10.1093/ajcp/28.1.56
  17. S. M. Robert, Preparative biotransformation, John Wiley and Sons, Chichester, New York, Brisbane, Toronto, Singapore, Edit, 1993.
  18. L. T. Kanerva, "Biocatalytic ways to optically active 2-amino-1-phenylethanols". Acta. Chim. Scand., 50, pp. 234-242, 1996. https://doi.org/10.3891/acta.chem.scand.50-0234
  19. N. Hoffmann, "Baekerhefe-ein lebendes Reagens fuer die organisch-chemische Synthese", Chemie in unserer Zeit, 30, pp. 201-213, 1996. https://doi.org/10.1002/ciuz.19960300411
  20. T. Langer, J. Janssen and G. Helmchen, Catalytic asymmetric hydrosilylation of ketons using rhodium(I)-complex of chiral phosphinooxazoline ligands, Tetrahedron Asymmetry, 7, pp. 1599-1602, 1996. https://doi.org/10.1016/0957-4166(96)00192-9
  21. G. Zhiwei, C. Yijun, G. Animesh, L.H. Ronald and N. P. Ramesh, Synthesis of ethyl and t-butyl (3R,5S)-dihydroxy-6-benzyloxy hexanoates via diastereoand enantioselective microbial reduction, Tetrahedron, 17, pp. 1589-1602, 2006. https://doi.org/10.1016/j.tetasy.2006.05.027
  22. S. H. Kyung, "Synthesis and application of new type organometallic catalyszt. Synthesis of bisphosphonite -rhodium complexes", Agricultural Chem. Biotechnology, 40, pp. 588-592, 1997.
  23. I. Avisar, J. G. Brook and E. Wolfovitz, "Atorvastatin monotherapy vs. combination therapy in the management of patients with combined hyperlipidemia", European J. Int. Med., 19, pp. 203-208, 2008. https://doi.org/10.1016/j.ejim.2007.09.004
  24. M. Arca, S. Natoli, F. Micheletta, S. Riggi, E. D. Angelantonio, A. Montali, T. M. Antonini, R. Antonini, U. Diczfalusy and L. Iuliano, "Increased plasma levels of oxysterols, in vivo markers of oxidative stress, in patients with familial combined hyperlipidemia: Reduction during atorvastatin and fenofiberate therapy", Free Radical Bio. Med., 42, pp. 698-705, 2007. https://doi.org/10.1016/j.freeradbiomed.2006.12.013
  25. K. Hiromi, D. Shoko, D. Kentaro, Y. Toru, O Yasuyuki, O. Yoshio, K. Tomoko, I. Yoshio, M. Tohru and A. Koji, "Protection against ischemic stroke damage by synergistic treatment with amlodipine plus atorvastatin in Zucker metabolic rat", Brain Research, 1382, pp. 308-314, 2011. https://doi.org/10.1016/j.brainres.2011.01.062
  26. A. M. Gott and J. A. Farmer, "Drug insight: The role of statins in combination with ezetimibe to lower Ldl-cholesterol", Nat. Clin. Pract. Cardiovasc. Med., 3, pp. 664-672, 2006. https://doi.org/10.1038/ncpcardio0711
  27. H. G. Song and H. Lee, "The effect of Persicae semen herbal-acupuncture at GB34 (Yangneungcheon) on a rat model of hyperlipidemia", J. Korean Oriental Med., 32, pp. 151-163, 2011.
  28. R. Scranton, H. D. Sessp, M. J. Stampfer, J. W. Levenson, J. E. Buring, J. M. Gaziano, "Predictors of 14-year changes in the total cholesterol to high-density lipoprotein cholesterol ratio in men", Am. Heart J., 147, pp. 1033-1038, 2004. https://doi.org/10.1016/j.ahj.2003.11.018
  29. G. Ji, X. Zhao, L. Leng, P. Liu and Z. Jiang, "Comparison of dietary control and atorvastatin on high fat diet induced hepatic steatosis and hyperlipidemia in rats", Lipids Health Dis.,10, pp. 23-32, 2011. https://doi.org/10.1186/1476-511X-10-23
  30. J. J. Lee, T. M. Ha, Y. M. Lee, A. R. Kim and M. Y. Lee, "Effect of Brassica rapa sprouts on lipid metabolism in rats fed high fat diet", J. Korean Soc. Food Sci. Nutr., 39, pp. 669-676, 2010. https://doi.org/10.3746/jkfn.2010.39.5.669