Protective action of dibenzocyclooctene lignans isolated from schizandrae against liver injury and its mechanism 3. 2 Antioxidant activity o

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1 PROGRESS IN CHEMISTRY Vol. 21 No. 1 Jan., ( ) 20 70,,,20 :,,,,,,, (DDB) (bicyclol) : R284 ; R ; R962 : A : X(2009) The Structure2Activity Relationship of Dibenzo ( a,c) cyclooctene Lignans Isolated from Fructus schiza ndrae and Innovation of Novel Anti2Hepatitis Drugs Yu Linghong Liu Gengtao 3 ( Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing , China) Abstract Fructus schizandrae (FS) has been used as a corroborative for about two thousands of years in traditional Chinese medicines. In the early 1970 s, Chinese clinicians found that the whole powder and the honey pill of FS improved the abnormal liver function of chronic viral hepatitis. pharmacology of FS are systematically studied in authorπs institute. Following this clinical lead, the chemistry and Twenty dibenzo ( a, c) cyclooctene lignans are isolated from different species of FS. The lignans have multiple pharmacological actions, mainly against liver injury, antioxidant, enhancing detoxification function, stimulating protein and glycogen biosynthesis, overcome multidrug resistance of cancer cells to chemotherapy as well as sedation on the central nervous system. Based on the study of the pharmacology and chemistry of FS, two novel anti2hepatitis drugs (DDB and bicyclol) are sequentially created through synthesizing analogues of schizandrin C, the most effective component of FS in anti2liver injury. The pharmacological action of different lignans and the relationship between structure and activity are reviewed in this paper. Key words Fructus schizandrae ; dibenzo ( a, c ) cyclooctene lignans ; liver injury ; hepatitis ; bicyclol ; anti2oxidative stress Contents 1 Introduction 2 Chemical constituents of Fructus schizandrae (FS) 3 The structure2activity relationship of dibenzo ( a, c) cyclooctene lignans isolated from FS : ( ) 3 e2mail ac. cn

Linghong Liu Gengtao 3 ( Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China) Abstract Fructus schizandrae (FS) has been used as a

2 Protective action of dibenzocyclooctene lignans isolated from schizandrae against liver injury and its mechanism 3. 2 Antioxidant activity of the dibenzocyclooctene lignans isolated from FS 3. 3 Protective effect of Sal on ox2ldl induced bovine aortic endothelium damage and oxidative induced neurotoxicity stress 3. 4 Enhancing liver detoxification function induction of the hepatic microsomal cytochrome P Stimulation of protein biosynthesis and glycogenesis in liver 3. 6 Inhibitory effect on the central nervous system 3. 7 Reversal multi2drug resistance to anti2cancer drugs 3. 8 Summary 4 Synthesis of dibenzo (a, c) cyclooctene lignans and derivatives and innovation of novel anti2hepatitis drugs 4. 1 Innovation of novel DDB as anti2hepatitis drug 4. 2 Innovation of second generative anti2hepatitis drug bicyclol 5 Perspective,, (DDB) ( bicyclol) [4 ] 2,, 2 2 ; Vc ;, C E 15 92,26 (dibenzocyclooctene) 1 3,,, , : ,, (CCl 4 ),,,,,, 20 50,, 20 70,, (ALT) (AST), 1973 [ ] 7 ( ), 10gΠkg, ALT,, ;,,, CCl 4,,,,ALT [5 ],,,,,

4 Enhancing liver detoxification function induction of the hepatic microsomal cytochrome P450 3. 5 Stimulation of protein biosynthesis and glycogenesis in liver 3.

3 , [ ] 18, 10 9 (1) : (SinA) ( ) ( ( ) SinB) R ( + ) ( R ( + ) SinB) S( ) ( S ( ) SinB) R ( + ) ( R ( + ) SinC) S ( ) ( S ( ) SinC) (SolA) (SolB) (Sal) [1 3 ] 1 9 [1 Fig. 1 Chemical structures of 9 kinds of dibenzo (a,c) cyclooctene lignans 3 ] 0. 1 %CCl 4 210mlΠkg, 24h ALT [6 ] ( ) SinB S ( ) SinB R ( + ) SinB ( ) SinC R ( + ) SinC S ( ) SinC SolB, CCl 4 14 C2CCl 4, CCl 4 (SerB) M( R ( + ) GmM1) R ( + ), M ( R ( + ) AgM1) (MDA), 14 C2CCl 4 R (AgnR) ( ) ( Rsn) Sal [7 ], 5 SinA SolA MDA (SerA) (SalB) ( Pgn) CCl 4 P2450,SinC CCl SolB SerB 50mgΠkg ALT, SolB 3,, NADPH, CCl 4 SinB, CCl 4 CCl 4 (CCl 4 ) P2450 ( CCl 3 ),,,,, ALT AST (LDH) CCl 4 NADPH,SinB 1mmolΠL NADPH,,CCl 4, CCl 3

1 %CCl 4 210mlΠkg, 24h 18 13 ALT [6 ] ( ) SinB S ( ) SinB R ( + ) SinB ( ) SinC R ( + ) SinC S ( ) SinC SolB, CCl 4 14 C2CCl 4, CCl 4 (SerB) M( R ( + ) GmM1) R ( + ), M ( R ( +

4 1 69 P2450 CCl 3, ALT, : ( O O ),ALT ;S2 R ; ( OH) > ( OCH 3 ) > ALT < ( OH) > ( COOH) 3. 2 (O 2 ) ( OH)H 2 O 2,,,,,,,, (PD) (AD),, CCl 4, C2NADPH C NADPH,, O 2, ( Fe 2 + ) O 2, O 2 H 2 O 2 OH, (MDA), 9,C2 NADPH Fe 2 + 2, MDA 9 1mmolΠL MDA, Sal ( ) SinB R ( + ) SinB S ( ) SinB R ( + ) SinC S ( ) SinC SinA MDA E, [8 1mmolΠL Sal MDA 100 % 10 ] (1) ,,,,50 % 15mlΠkg,12h MDA gΠkg Sal SinB 200mgΠkg,MDA SolA SolB, MDA, [9 ] C2 [8 NADPH (MDA ) 10 ] Table 1 Effect of 9 kinds of dibenzocyclooctene lignans on lipid peroxidation ( MDA formation ) induced by iron2cysteine and ascorbate2nadph as well as on superoxide anion (O 2 ) generation [8 in xanthine2xanthine oxidase system 10 ] lignan(1 molπl) ascorbate2nadph % of inhibition MDA Vit E 60 3 Sal S ( ) Sin C R ( + ) Sin C S ( ) Sin B R ( + ) Sin B ( ) Sin B Sin A Sol A Sol B 20 8 iron2cysteine Sal, Fe 2 + 2, MDA ATP, Sal 1mmolΠL MDA ATP,

+ ) SinC S ( ) SinC SinA MDA E, [8 1mmolΠL Sal MDA 100 % 10 ] (1) 3. 2.

5 70 21,, MDA,ATP, Sal 1mmolΠL, [11 ] (adriamycin),,,h 2 O 2, Sal?, Sal 1mmolΠL,, MDA ATP, ( ESR),Sal, H 2 O 2 Sal [12 ] Sal Sal SinB ESR, Sal SinB O 2 OH [13 ], S R,,MDA ,, (SOD) ( GSHPX),,O 2 OH H 2 O 2 (LOO )? SinB 200mgΠkg, 3, (cytosol) SOD [9 ],O 2 OHH 2 O 2, H 2 O 2, H 2 O 2,,Sal SinB SinC H 2 O 2 MDA [8 ], : (1) O 2 OH ; (2) H 2 O 2 ; (3) SOD,,, 2 2 Fig. 2 Sites of the action of schizandrins on free radical reaction ,, 8, : SinAR ( + ) SinB S ( ) SinB R ( + ) SinCS ( ) SinCSolASolB Sal MMX, AM1, B3LYP 6231G,, O H, :, [14 ] ( OH), OH, OH, (Fe 2 + ) OH,8,,O O,

2 Sites of the action of schizandrins on free radical reaction 3. 2.

6 1 71, O,,O OH : S ( ) SinCR ( + ) SinC > SolB > S ( ) SinB > Sal > R ( + ) SinB > SinA > SolA (O g 2 ), OH,, O g 2 O g 2,, C Sal, 7, O g 2, C O g 2, C O g 2 :SolB > S ( ) SinC > R ( + ) SinC > S ( ) SinB > R ( + ) SinB > SolA > SinA > Sal Sal O g 2,Sal 2, O g 2 2, (R ) (RO ) (ROO ),,, O H Sal O H 2, Sal 2,C H O H,,:,,, ;, S ( ) R ( + ) Sal OH O g 2 (), O g 2, Sal 2E,, (3) 3 3 Fig. 3 Chemical Structures of antioxidants designed by quantum chemistry (molecular modeling) 4,,, 4, ( E max 2PHOB),, E max 2PHOB,, E max 2PHOB Sal E max 2PHOB (4), Sal (2), 2 4 C2NADPH Table 2 The surface hydrophobicity of 4 kinds of lignans and their inhibition effect on microsomal lipid peroxidation induced by ascorbate2nadph system compound ascorbate2nadph MDA % inhibition E max 2PHOB! Sal R ( + ) SinC Sol A Sol B (Sal) (ox2ldl),, PD AD (LDL) ox2ldl

3 Chemical Structures of antioxidants designed by quantum chemistry 3. 2.

7 72 21 ( benzo ( a, c) 4 (molecular modeling) 4 pyrene),, (SerA) Fig. 4 Surface hydrophobicity of 4 kinds of schizandrins (SerB) SinB SolB calculated by molecular modeling [16 P ], SinB P450, (: 20 80,,, P450 ), SinB SolB, Sal 3 H2 Sal LDL ox2ldl 3 H2(estradiol) 3H2,,Sal (100 10M) (mutagenecity) LDL,, LDL E [14 ],Sal 50M 10M ox2ldl,ox2ldl, ROS, [15 ] ox2ldl NG108215,, (LDH),10M Sal, LDH, ROS C, Sal 3. 4 P450,,, P450,,,,CCl 4 P450,,,?, SinA SinB SinC SolB Sal 200mgΠkg, 3, P450 NADPH2 P450, SinB SolB

P450, (: 20 80,,, P450 ), SinB SolB, Sal 3 H2 Sal LDL ox2ldl 3 H2(estradiol) 3H2,,Sal (100 10M) (mutagenecity) LDL,, LDL E [14

8 1 73 P450 P450,,, P450,, P450 [19 ] 3. 5, SinB SinB 100mgΠkg, 3, 10gΠkg, 4, 14 C2, [5 ] 20h 10 % 20mlΠkg, 24h SinB SolB SolA SinA 100mgΠkg,1h 20 % 10mlΠkg,,SinB, SinB [20 ], SolB, SinC, 3. 6,,SolA MDR, SolB, SinA (DDB) SolA SolA,,10mgΠkg 115mgΠkg,1mgΠkg,, 100mgΠkg 3mgΠkg, [21 ] SolA, SolA SolB,SolA SolB OH, OH, SolA SolB,, SinB SinC,,, 3. 7 (multidrug resistance,mdr),,, MDR,,,, mdr1 P2 (P2gp), P2gp, MDR (LCC) SinA ( KBv200, MCF2 dox) Bel7402 MDR ( ), P2gp SinA LCC MDR,KBv200 ; [22 ] SinA MDR, SinA LCC MDR, SolA SinC SinB SolB Sal,, SinA Sal ( OCH3 OH),SolA SolA 8 ( OH), SinA 3. 8, : (1) ; (2), ; (3) ; (4),; (5)

6,,SolA MDR, SolB, SinA (DDB) SolA SolA,,10mgΠkg 115mgΠkg,1mgΠkg,, 100mgΠkg 3mgΠkg, [21 ] SolA, SolA SolB,SolA SolB OH, OH, SolA SolB,, SinB SinC,,, 3.

9 74 21, ; (6) (5) 5 Fig. 5 Illustration of the pharmacological actions of Fructus schizandrae (DDB),:4,4 2 25,6,5,6 2 22,2 2(biphenyl dimethyl dicarboxylate), DDB,6DDB 1972,7, 5 CCl 4, SinC 1974 SinC,DDB,,, 5 CCl 4, 6 DDB Fig. 6 Fructus schizandrae and chemical structures of anti2hepatitis drug DDB and bicyclol DDB, [23 ] DDB ALT,,1983,DDB,,, 4. 2 DDB,,,, DDB 2 DDB,, DDB,,DDB 4,4 2 25,6,5,6 2() (bicyclol),,,,,,, [24,25 ] , GCP(good clinical practice), [26 28 ]

10 1 75,, ALT AST 2, HBeAg HBV DNA, 25mg, 3,, 6, 3, ALT AST, 50 %,HBeAg HBV DNA,e,,,ALT 200, HBeAg e,,,,, ALT 60 %,, %, HCV RNA, DDB bicyclol,,2004 9,,,,,,,,,, ( HBV DNA),,,,,,,,,, 15,,,, 5,,,,,,,,,,, [ 1 ] (Chen Y Y), (Shu Z B), (Li L N). (Sci. Chin. ), 1976, (1) : [ 2 ] ( Chen Y Y), ( Yang Y Q). ( Acta Pharmacutica Sinica), 1982, 17 : [ 3 ] Li L N. Planta Med., 1985, [ 4 ] (Liu G T). (Acta Pharmaceutica Sinica), 1983, 18 (9) : [ 5 ] Liu G T. Chin. Med. J., 1989, 102 : [ 6 ] Liu G T. Proceedings of TMMP. The People s Medical Publishing House, Beijing, 1987, 78 [ 7 ] Liu K T, Lesca P. Chem. Boil. Interact., 1982, 41 : [ 8 ] (Lu H), (Liu G T). (Collected Theses on the Occasion of 30th Anniversary of the Founding of CAMS) [ 9 ] Lu H, Liu G T. Chem. Biol. Interact., 1991, 78 : [10 ] Lu H, Liu G T. Planta Med., 1992, 58 : [11 ] (Lin T J), (Liu G T). (Chin. J. Pharmacol. Toxicol. ), 1991, [12 ] Lin T J, Liu G T. Li XJ, et al. Acta Pharmacol. Sin., 1990, 11 : [13 ] Li X J, Zhao B L, Liu G T. Xin W J. Free Rad. Biol. Med.,

, 1985, 297 299 [ 4 ] (Liu G T). (Acta Pharmaceutica Sinica), 1983, 18 (9) : 714 718 [ 5 ] Liu G T. Chin. Med. J., 1989, 102 : 740 749 [ 6 ] Liu G T. Proceedings of TMMP.

11 , 9 : [14 ] Yu L H, Sun Y M, Zhang H Y, Liu G T. Acta Pharmacol. Sin., 2004, 25 (8) : [15 ] Yu L H, Liu G T. J. Asian Nat. Prod. Res., 2008, 10 (8) : [16 ] Wei H L, Liu G T. Acta Pharmacol. Sin., 1985, 6 (1) : [17 ] Liu K T, Crestell T, Provost E Le, Lesca P. Biochem. Biophys Res. Common., 1981, 103 (4) : [18 ] Li Y, Liu G T. Acta Pharmacol. Sin., 1987, 8 (6) : [19 ] Liu G T. Drug Metab. Rev., 1991, 23 (3Π4) : [20 ] Bao T T, Xu G F, Liu G T, Wei H L, Song Z Y. Chin. Med. J. ( Engl. ), 1980, 93 : [21 ] (Bian ZJ), (Ren Z H), (Niu X Y). (Acta Pharmacol. Sin. ), 1983, 18 (6) : [22 ] Huang M, Jin J, Sun H, Liu G T. Cancer Chemother. Pharmacol., 2008, 62 : [23 ] (Xie J X), (Zhou J), (Zhang C Z), ( Yang J H). (Acta Pharmaceutica Sinica), 1982, 17 (1) : [24 ] Liu G T. Chin. J. New Drugs, 2001, 10 : [25 ] Liu G T. Med. Chem., In press [26 ] ( Yao GB), (Ji Y Y), (Wang Q H). ( Chin. New Drug Clinic Remedies), 2002, 21 : [27 ] ( Yao GB), (Ji Y Y), (Wang Q H). (National Med. J. China), 2002, 82 : [28 ] ( Yao G B), (Xu D Z), (Lan P). ( Chin. New Drug Clini. Remedies), 2005, 24 :

, 1981, 103 (4) : 1131 1135 [18 ] Li Y, Liu G T. Acta Pharmacol. Sin., 1987, 8 (6) : 560 564 [19 ] Liu G T. Drug Metab. Rev.

TGF-β AngⅡ B SD ~ 220g SPF. SCXK No SYXK ~ 25 40% ~ 70% OR37G-C

TGF-β AngⅡ B SD ~ 220g SPF. SCXK No SYXK ~ 25 40% ~ 70% OR37G-C 2017 7 43 4 Journal of Southwest Minzu University Natural Science Edition Jul. 2017 Vol. 43 No. 4 doi10. 11920 /xnmdzk. 2017. 04. 008 1 1 1 2 1 1 3 1. 610212 2. 6100413. 610031 AngⅡ TGF-β. SD 60 180 ~