化学-酶催化制备天然丹参素

doi:10.11944/j.issn.1000-0518.2016.09.150444

摘要/Abstract

摘要：

丹参素是中药丹参的水溶性化学成分之一,具有很多潜在的药理活性。以3,4-二羟基苯甲醛和乙酰甘氨酸为原料,经Erlenmeyer反应并开环得到α-乙酰氨基-β-(3,4-二乙酰氧基苯基)丙烯酸、盐酸水解制得β-(3,4-二羟基苯基)丙酮酸,再经乳酸片球菌1.2696静息细胞生物酶催化还原合成了天然右旋丹参素,总收率69.4%,丹参素对映体过量值97.5%。

关键词: 乳酸片球菌静息细胞, 化学-酶催化合成, 丹参素

Abstract:

Danshensu is one of water-soluble components in Chinese medicine Danshen(Salvia miltiorrhiza bunge) and has some potential pharmaceutical activities. Danshensu was prepared through chemoenzymatic synthesis starting from the Erlenmeyer condensation of 3,4-dihydroxybenzaldehyde and acetyl glycine and followed by ring opening reaction to give α-acetamino-β-(3,4-diacetoxylphenyl)acrylic acid. Hydrolysis of the substituted acrylic acid with hydrochloric acid gave β-(3,4-dihydroxyphenyl) pyruvate. Finally, Danshensu was obtained by enzymatic reduction of β-(3,4-dihydroxyphenyl) pyruvate with resting cells of pediococcus acidilactici. The overall yield is 69.4% and the optical purity of Danshensu is 97.5% ee.

Key words: resting cells of pediococcus acidilactici, chemoenzymatic synthesis, Danshensu

杨玲英, 曾庆友, 杨道茂. 化学-酶催化制备天然丹参素[J]. 应用化学, 2016, 33(9): 1073-1078.

YANG Lingying, ZENG Qingyou, YANG Daomao. Chemoenzymatic Synthesis of Danshensu[J]. Chinese Journal of Applied Chemistry, 2016, 33(9): 1073-1078.

参考文献

[1]	Chang J Y,Chang C Y,Kuo C C,et al.Salvinal, a Novel Microtubule Inhibitor Isolated from Salvia Miltiorrhizae Bunge(Danshen), with Antimitotic Activity in Multidrug-sensitive and Resistant Human Tumor Cells[J]. Mol Pharmacol,2004,65(1):77-84.
[2]	Husna B,On T,Zhu Y Z. Effects of Purified Salvia Miltiorrhiza Extract on Cardiac Vascular Smooth Muscle Hypoxic Cells[J]. J Pharmacol Sci,2007,104(3):202-211.
[3]	Vergara-Salinas J R,Pérez-Jiménez J,Torres J L,et al. Effects of Temperature and Time on Polyphenolic Content and Antioxidant Activity in the Pressurized Hot Water Extraction of Deodorised Thyme(Thymus Vulgaris)[J]. J Agric Food Chem,2012,60(44):10920-10929.
[4]	Wang M,Sun G B,Sun X,et al.Cardioprotective Effect of Salvianolic Acid B Against Arsenic Trioxide-induced Injury in Cardiac H9c2 Cells via the PI3K/Akt Signal Pathway[J]. Toxicol Lett,2013,216(2/3):100-107.
[5]	Ding M,Ye T X,Zhao G R,et al.Aqueous Extract of Salvia Miltiorrhiza Attenuates Increased Endothelial Permeability Induced by Tumor Necrosis Factor-Alpha[J]. Int Immunopharmacol,2005,5(11):1641-1651.
[6]	HU Fengguo,DENG Yongjian. The Search of Danshen Water-soluble Compositionses Makes Progress[J]. Primary J Chinese Mater Med,2014,3(7):176-178(in Chinese). 胡凤国,邓永建. 丹参水溶性成分的研究进展[J]. 基层中药杂志,2014,3(7):176-178.
[7]	DING Jie,YU Zemin,DING Keyi. Synthesis of Danshensu[J]. J Southwest Univ Nat(Nat Sci Ed),2015,41(1):50-53(in Chinese). 丁杰,余泽民,丁克毅. 丹参素的合成工艺研究[J]. 西南民族大学学报:自然科学版,2015,41(1):50-53.
[8]	DENG Xiling,CHEN Xuemin,JIANG Fashou,et al.Synthesis of Sodium β-(3,4-Dihydroxyphenyl) lactate[J]. Chinese J Pharm,2005,9(9):523-524(in Chinese). 邓喜玲,陈学敏,江发寿,等. 丹参素的合成[J]. 中国医药工业杂志,2005,9(9):523-524.
[9]	Chen M,Chen H,Wang Y,et al.Efficient and Practical Asymmetric Synthesis of Isopropyl (R)-3-(3',4'-dihydroxyphenyl)-2-hydroxypropanoate and Its Enantiomer[J]. Tetrahedron:Asymmetry,2011,22(1):4-7.
[10]	XUE Fen,DAI Huajuan,DING Lirong. Synthesis of Sodium β-3,4-Dihydroxyphenyl Lactate “Danshensu”[J]. Acta Acad Med Primae Shanghai,1983,10(2):133-135(in Chinese). 薛芬,戴华娟,丁丽蓉. 丹参素[β-(3,4-二羟基苯基)乳酸钠]的合成[J]. 上海第一医学院学报,1983,10(2):133-135.
[11]	Wong H N C,Xu Z L,Chang H M,et al. A Modified Synthesis of (±)-β-Aryllactic Acids[J]. Synthesis,1992,1992(8):793-797.
[12]	Eicher T, Ott M, Speicher A. Bryophyte Constituents;7:New Synthesis of (+)-Rosmarinic Acid and Related Compounds[J]. Synthesis,1996,1996(6):755-762.
[13]	Bubl E C,Butts J S. A Method of Synthesis of Phenyllactic Acid and Substituted Phenyllactic Acids[J]. J Am Chem Soc,1951,73(10):4972-4972.
[14]	LI Xiaoling,SHAN Yuqing,ZHANG Qunzheng,et al.Synthetic Methods of Danshensu and Its Derivatives[J]. Chinese J Pharm,2008,17(10):17-19(in Chinese). 李小玲,单玉庆,张群正,等. 丹参素及其衍生物的合成方法[J]. 中国药业,2008,17(10):17-19.
[15]	Dong C,Wang Y, Zhu Y Z. Asymmetric Synthesis and Biological Evaluation of Danshensu Derivatives as Anti-Myocardial Ischemia Drug Candidates[J]. Bioorg Med Chem,2009,17(9): 3499-3507.
[16]	TONG Yuanfeng,GUO Xiaoyun. CHENG Yonghao,et al.Synthesis of dl-tanshinol[J]. Chinese J Med Chem,2007,17(2):92-94(in Chinese). 童元峰,郭晓赟,程永浩,等. Dl-丹参素的合成[J]. 中国药物化学杂志,2007,17(2):92-94.
[17]	ZHANG Qunzheng,DONG Yan,NAN Yefei,et al.Synthesis of β-(3,4-Dihydroxyphenyl)-α-hydroxy Propionic Acid Esters[J]. Chinese J Org Chem,2009,29(9):1466-1469(in Chinese). 张群正,董岩,南叶飞,等. β-(3,4-二羟基苯基)-α-羟基丙酸异丙酯/冰片酯合成研究[J]. 有机化学,2009,29(9):1466-1469.
[18]	SUN Ju,GU Jun,LI Lingzhi. Synthesis of Danshensu Derivatives[J]. Chinese J Synth Chem,2010,18(2):215-218(in Chinese). 孙举,顾军,李灵芝. 丹参素衍生物的合成[J]. 合成化学,2010,18(2):215-218.
[19]	Bai Y,Zhang Q,Jia P,et al.Improved Process for Pilot-Scale Synthesis of Danshensu((±)-DSS) and Its Enantiomer Derivatives[J]. Org Process Res Dev,2014,18(12):1667-1673.
[20]	LIU Pei,QIN Fanggang,BAI Yajun,et al.Synthesis and Chiral Separation of Isopropyl and Bornyl β-(3,4-Dihydroxyphenyl)-α-Hydroxypropionate[J]. J Northwest Univ,2015,45(3):413-417(in Chinese). 刘佩,秦方刚,白亚军,等. 丹参素异丙酯/冰片酯的合成及手性拆分研究[J]. 西北大学学报,2015,45(3):413-417.
[21]	ZHOU Xiaoming,XUE Fen,LOU Yaping,et al.Asymmetric Synthesis of Optically Active β-Phenyl Latic Acid and Its Methyl Ester[J]. Acta Acad Med Primae Shanghai,1988,15(2):155-160(in Chinese). 周小鸣,薛芬,楼亚平,等. 用不对称环氧化合成光学活性β-苯基乳酸及其甲酯[J]. 上海第一医学院学报,1988,15(2):155-160.
[22]	JIANG Ru,CHEN Hui,LIU Xueying,et al. Asymmetric Synthesis of (+)-Danshensu[P],CN 102924265A,2013-02-13(in Chinese). 姜茹,陈惠,刘雪英,等. (+)-丹参素的不对称合成方法[P],CN 102924265A,2013-02-13.
[23]	TIAN Hailin,ZHOU Xiaowei,CHEN Ming,et al.Asymmetric Synthesis of Danshensuborneol Ester[J]. Chinese J Med Chem,2012,22(2):113-116(in Chinese). 田海林,周晓伟,陈明,等. 丹参素冰片酯不对称合成研究[J]. 中国药物化学杂志,2012,22(2):113-116.
[24]	Simon R C,Mutti F G,Kroutil W. Biocatalytic Synthesis of Enantiopure Building Blocks for Pharmaceuticals[J]. Drug Discovery Today:Technol,2013,10(1):37-44.
[25]	Patel R N. Synthesis of Chiral Pharmaceutical Intermediates by Biocatalysis[J]. Coord Chem Rev,2008,252(5):659-701.
[26]	Wang H,Zong M H,Wu H,et al.Novel and Highly Regioselective Route for Synthesis of 5-Fluorouridine Lipophilic Ester Derivatives by Lipozyme TLIM[J]. J Biotechnol,2007,129(4):689-695.
[27]	ZHAO Shuling,GU Yaohua,XUE Ping. Recent Progress on Chemo-enzymatic Synthesis of Chiral Compounds with High Stereoselectivity[J]. Chem Res Appl,2014,26(4):473-382(in Chinese). 赵淑玲,谷耀华,薛屏. 化学-酶法高选择性合成手性化合物的研究进展[J]. 化学研究与应用,2014,26(4):473-382.
[28]	Güvenalp Z,Ströch K,Demirezer L,et al.Phytochemical and Antimicrobial Investigation of Echium Vulgare Growing in Turkey[J]. Biochem Syst Ecol,2004,32(9):833-836.
[29]	XIE Fei,ZHOU Xinbo,GUO Jiqian,et al.Chiral Separation of Danshensu en Antiomers by HPLC[J]. Chinese J Pharm Anal,2014,(4):664-668(in Chinese). 谢菲,周辛波,郭继倩,等. 高效液相色谱法手性拆分丹参素对映体的研究[J]. 药物分析杂志,2014,(4):664-668.
[30]	Wang Z,Chen Z D,Li D. Biotransformation of Phytosterol to Produce Androsta-Diene-Dione by Resting Cells of Mycobacterium in Cloud Point System[J]. Process Biochem,2006,41(3):557-561.
[31]	Goldberg K,Schroer K,Lütz S,et al.Biocatalytic Ketone Reduction-A Powerful Tool for the Production of Chiral Alcohols-Part II:Whole-Cell Reductions[J]. Appl Microbiol Biotechnol,2007,76(2):249-255.
[32]	HUANG He,YANG Zhonghua,YAO Shanjing. Asymmetric Reduction Carboonyl Compounds to Chrial Alcohols by Baker's Yeast[J]. Chinese J Bioprocess Eng,2004,2(2):52-55(in Chinese). 黄和,杨忠华,姚善泾. 面包酵母催化羰基不对称还原合成手性醇的研究[J]. 生物加工过程,2004,2(2):52-55.