Phytochemistry and Quality Control of Black Cohosh (Actaea

Chapter 5

Downloaded by UNIV OF PITTSBURGH on December 24, 2014 | http://pubs.acs.org Publication Date: September 1, 2008 | doi: 10.1021/bk-2008-0987.ch005

Phytochemistry and Quality Control of Black Cohosh (Actaea racemosa), Medicinal Cimicifuga Species and Their Derived Products 1

2

2

1

Liang Zhou , Qing-Li Wu , James E. Simon , Chun-Yu Liu , Jun-Shan Yang , and Yong-Hong Liao 1

1

2

1

Institute of Medicinal Plant Development ( I M P L A D ) , Chinese Academy of Medical Sciences and Peking Union Medical College, Xi Bei Wang, H a i Dian District, Beijing 100094, People's Republic of China New Use Agriculture and Natural Plant Products Program, Department of Plant Biology and Plant Pathology, Rutgers, The State University of New Jersey, 59 Dudley Road, New Brunswick, NJ 08901

Black Cohosh, Actaea racemes L . formerly known as Cimicifuga racemosa L . , and other medicinal Cimicifuga species and their derived products have been used for the treatment of menopausal disorders and other conditions. Phytochemical studies on medicinal Cimicifuga species have led to the isolation and structural elucidation of over 180 compounds, mainly triterpene glycosides and phenolics. Numerous analytical methods have been developed for the qualitative and quantitative analysis of main bio-active compounds in black cohosh and Cimicifuga plants and derived products yet their analysis for quality control and quantitation remains challenging. This article reviews the advances in the phytochemistry and analytical methods concerning Cimicifuga species and derived products, with a particular view in summarizing the feasibility of using chemical assays for the purpose of quality control, such as the tests of identity, quantity and stability, for Cimicifuga herbs and derived products.

© 2008 American Chemical Society

In Dietary Supplements; Ho, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2008.

59


60 Black cohosh (Actaea racemosa L., formerly classified as Cimicifuga racemosa L.,) is a perennial herb in the Ranunculaceae family and native to North America. The roots and rhizomes have traditionally been used for gynecological complaints and rattlesnake bites by Native Americans. Currently, many black cohosh derived preparations are commercially available as either herbal medicinal products or dietary supplements for the treatment of menopausal disorders in Europe and America. In Asia, the rhizomes of other Cimicifuga species herbs, such as G dahurica, C foetida, C. heracleifolia, C. japonica, C acerina and C. simplex, have also been used in traditional or folk medicine systems. The former three species are used in traditional Chinese medicine as "Sheng-ma" and recorded in Pharmacopoeia of the People's Republic of China (7) for inducing the eruption of measles at the onset of symptoms, and the treatment of headache due to pathogenic "windheat", sore throat, and uterine and rectal prolapses. Phytochemical studies on medicinal Cimicifuga species have led to the isolation and structural elucidation of over 180 compounds, many being triterpene glycosides and phenolics. However, despite the extensive number of pharmacological and clinical studies which have been conducted on these species, neither the active principles nor the mode of action of black cohosh and other related species are well understood. As a result, the commercial black cohosh products are generally standardized based on the total content of triterpene glycosides, calculated as 23-epi-26-deoxyactein (117), whereas ferulic acid (168) and isoferulic acid (169) are utilized as markers for qualitative and quantitative analysis of "Shengma" as described in Pharmacopoeia of the People's Republic of China (/). The present paper focuses on the advances in the phytochemistry and analytical methods concerning black cohosh and Cimicifuga species and derived products, with a particular view in providing an assessment on the various methods used in the determination of quality and natural product content. In this review, we use the former name of Cimicifuga rather than Actaea to avoid confusion with the published literature.

Chemical Components from Medicinal Cimicifuga Species Many types of phytochemical compounds including cyclolanstane triterpenes mid their glycosides, aromatic acids and related derivatives, chromones and other compounds, have been isolated and elucidated from Cimicifuga plants.

Cyclolanstane Triterpenes and Their Glycosides Triterpenes and their glycosides have been regarded as basic and characteristic components in Cimicifuga plants and have drawn considerable attention. Approximately 150 compounds (1-150) of this type (Table I, for



61 structures of compounds, see Scheme 1) have been isolated from Cimicifuga species, mainly coming from the rhizomes of C racemosa, C. simplex, Cfoetida and C. dahurica. A l l of these compounds belong to 9,19-cyclolanostane triterpenes, with a 9,19-cyclopropane in ring B and a side-chain being generally highly oxygenated. In addition, the sugar moieties of the glycosides are mostly xylose, together with glucose, arabinose and galactose. The largest group of cyclolanstane triterpenes reported contain cimigenol (1) as an aglycone. O f these type of compounds, cimigenol xyloside (2), detected in many Cimicifuga species, has often been referred to in many published papers as cimicifugoside. However, in our review, cimicifugoside is referred to compound 126. The triterpene glycoside containing extracts of C. foetide and C. racemosa have been extensively studied in vitro, in vivo and some clinical trials, in particular on their role in the relief of menopausal symptoms (see review 50). In addition, purified triterpene glycosides from Cimicifuga plants have also been reported to show various biological activities. For example, in an early study on the endocrine effects of the ingredients of C racemosa, actein (125) and cimigenol xyloside (2) were found to reduce the serum luteinizing hormone levels in vivo (51). In another study, cimigenol (1) and some related cycloartane triterpenoids appeared to inhibit Epstein-Barr virus early antigen ( E B V - E A ) activation in Raji cells (52). Purified triterpene glycosides were also found to display cytotoxicities (12,53,54), anti-HIV activity (55), antimalarial activity and nucleoside transport inhibitory activity (56).

Aromatic Acids and Related Derivatives Six aromatic acids (165-170) and 15 derived esters (151-164, 185) have presently been documented from Cimicifuga plants (Table II). These compounds have been demonstrated to show various biological activities including antioxidant (60,61), anti-inflammatory (62), vasoactivity (63), estrogenic activity (64), antihyperglycemic activity (65), and inhibiting neutrophil elastase activity and collagenolysis (66,67). The phenolic acids, in particular, ferulic acid (168) and isofurulic acid (169), are generally regarded as active principles of Cimicifuga herbs used as anti-inflammatory medicines.

Chromones and Other Compounds Ten chromones (171-180) (Table III) and several alkaloids (181-184) (73,74,75) have also been isolated from Cimicifuga species. A new cyclic guanidine alkaloid, cimipronidine (181), isolated from the fraction o f C.


62 Table I. Cyclolanostane Triterpenes and Their Glycosides from Cimicifuga Species No. Compound 1 cimigenol 2 cimigenol xyloside

3 25-0-acetylcimigenoside

Formula (MW) Source Ref. C30H48O5 (488) a,b 2,3,4 C35H 0 (620) b,c,g 3,5,6,7 56

9

C 7H O|0 3

58

a,b,c,e,g 5,6,7,8,9


(662)

4 25-0-acetylcimigenol-3-/?-DglucopyranosyH 1 ->3)-/?-Dxylopyranoside

(824)

5

C 5H 60,o

12/^hycfroxycimigenol-3-0-/?-D-

C H 0 4 3

3

6 8

e

1 5

5

b,c,e

xylopyranoside (636) 6 25-0-acetyl-12/^hydroxycimigenol- C 7H 80,i(678) g 3~0-a-L-arabinopyranoside 7 12/?,21-dihydroxycimigenol-3-0-a-L- C 5H560n(652) g arabinopyranoside 3

5

3

8

16,23/?: 16,245-diepoxy-

C H54O (634) e 35

I0

3J3,12ft,15 a,25-tetrahydroxy-cycloart7-ene-3-0-ar-L-arabinopyranoside 9 3-0-a-L-arabinopyran-cimigenol-15- C iH oOi (776) b O-yff-D-glupyranoside 4

10 12/^hydroxycimigenol-3-0-a-L-

11 12 13 14 15 16 17 18 19 20

6

4

C H O 3 5

5 6

1 0

c,e,g

arabinopyranoside (636) 7/^hydroxycimigenol-3-0-/?-DC H 6Oi b,e xylopyranoside (636) la-hydroxycimigenol-3-0-/?-DC H Oio e xylopyranoside (636) la-hydroxycimigenol-3-0-/?-DC H 8 0 (656) e galbinopyranoside 25-0-acetyl-7/«iydroxycimigenol-3- C H 5 0 n e O-^-D-xylopyranoside (678) 25-O-acetylcimigeol C H O (530) f 7,8-didehydrocimigenol-3-(9-^DC H O, (648) e galbinopyranoside cimigenol-3-0-/^D-galbinopyranoside C H Oio(650) c, e 25-0-methylcimigenol-3-O-/^DC H Oio(664) e galbinopyranoside 25-0-acethylcimigenol-3-0-^DC H6 O„ (692) e galbinopyranoside 25-0-acethylcimigenol-3-0-/J-DC H oO,,(692) e glubinopyranoside 35

5

0

35

56

3 6

5

37

8

3 2

5 0

36

56

36

58

37

60

38

38

n

6

0

0

6

9

6,10,11

12 12 13

4 10,11,12

4,11 14 14 11 15 14 10,14 16 16 16


63 Table I. Continued. Ref. Formula (MW) Source 6 b (752) 17 e 25-0-acetyl-lcr-hydroxycimigenol-3- C37H58O1I (678) O-yS-D-xylopyranoside 17 e C35H56O10 1 cr-hydroxycimigenol-3-0->5-D(636) xylopyranoside d 18 C35H56O1O 22-hydroxycimigenol-3-0-/?-D(636) xylopyranoside C H 0 ( 6 3 4 ) a, b, c,g 8,19 25-0-acetylcimigenol-3-0-/?-D-

No. Compound 21 cimisideB 22 23


24 25

C40H64O13

36

58

9

xylopyranoside C H580 (634) g 26 25-0-methylcimigenol-3-0-a-Larabinopyranoside c 27 cimigenol-3-0-/?-D-glubinopyranoside C36H Oio (650) C3 H 6O (636) g 28 cimiracemoside A C 5H56O (636)g 29 cimiracemoside B C 5H56O (620) g 30 cimiracemoside C 36

9

58

5

5

10

3

10

3

9

12,20 5 21 21 7,21

31 cimiracemoside D

C H gOn (678) 5

g

21

32 25-0-acetylcimigenol-3-0-/?-Dglucopyranosyl-( 1 -»2)-/?-dxylopyranoside 33 cimigenol-3-0-/?-D-glucopyranosyl(1 ->3)-/?-D-xy lopyranoside 34 cimigenol-3-0-/?-D-glucopyranosyl(1 ->2)-y#-D-xylopyranoside 35 cimigenol-3-O-yS-D-glucopyranosyl(l->2) -/^D-glucopyranosyl-(l->2)-/?D-xylopyranoside 36 12/^hydroxycimigenol-3-0-/?-Dgalactopyranoside 37 Cimigol 38 24-e/?/-7,8-didehydrocimigenol 39 3-keto-24-e/?/-7,8-didehydrocimigenol

C43H68O15

c

22

c

22

C41H66O14 (782)

c

23

C47H76O19

c

22

c

10

a,b,c f f f

24 15 15 15

40

2\4'-0-diacetyl-24-e/?/-7,8didehy drocimignol-3 -0-/2-Dxylopyranoside

37

(824) C41H66O14

(782)

(944) C36H5 On (666) C35H 0 (488) C oH460 (486) C30H44O5 (484) C39H58O11 (702) 8

48

3

5

5

Continued on next page.


64 Table I. Continued. No. Compound 41 3'-0-acetyl-24-e p/-7,8didehydrocimigenol-3-0-/?-Dxylopyranoside 42 24-e/?z-7,8-didehydrocimigenol-3- 0 >8-D-xylopyranoside 43 7,8-didehydrocimigenol-3-0-ar-Larabinopyranoside 44 25-0-acetyl-7,8-didehydrocimigenol3-0-yff-D-xylopyranoside 45 25-0-acetyl-7,8-didehydrocimigenol3-O-or-L-arabinopyranoside 46 25-anhydrocimigenol-3-0-/?-Dxylopyranoside 47 7,8-didehydrocimigenol 48 7,8-didehydrocimigenol-3-0-/?-Dxylopyranoside 49 25-0-acetyl-7,8-didehydrocimigeol 50 25-anhydrocimigenol-3-0-/?-Dgalactopyranoside 51 25-anhydrocimigenol-3-0-a-Larabinopyranoside 52 cimiracemoside J 53 cimiracemoside K 54 25-0-methyl-24-0acetylhydroshengmanol-3-O-^-Dxylopyranoside 55 25-0-methyl-7/^hydroxy-24-0acetylhydroshengmanol-3-0-)ff-Dxylopyranoside 56 25-0-methyl-la-hydroxy-24-0acetylhydroshengmanol-3-O-yff-Dxylopyranoside 57 7/?-hydroxy-24-0acetylhydroshengmanol-3-0-/?-Dxylopyranoside 58 7,8-didehydro-24-0acetylhydroshengmanol-3-O-yff-Dxylopyranoside


J

Formula (MW)

Source

Ref.

f

75

C 5H540 (618) f

15

C 5H540 (618) e

14

C 7H560io (660)

b,e

4,14

Q7H56O10

e

14

C37H56O10

(660) 3

9

3

9

3

(660) C H54O (602) c,g

5,7,25

C H46O (486) b , f C H540 (618) b,e

4,15 4,14

C H4 0 (528) b , f C H 0 (632) c

4,15 22

C H O (602) g

7

C H56O (660)g C H 6O (660)g C H 0„(694)e

7 7 26,27

C H 20i2 (710)

e

26

C H6 Oi2 (710)

e

26

C H O (696)e

16

C H 0„(678)f

15

35

8

30

5

35

9

32

36

35

8

56

54

37

37

38

37

3 7

9

8

10

5

3 8

38

6

I0

6 2

6

2

60

5 8

12


65


Table I. Continued. No. Compound 59 24-0-acetyI-7,8didehydroshengmanol-3-O-ar-Larabinopyranoside 60 24-0-acetyl-25-O-methyl-7,8didehydroshengmanol-3 xylopyranoside

Formula (MW) Source Ref. C H 5 8 0 (678) e 14

61 3-arabinosyl-24-0acetylhydroshengmanol-15-0-/J-Dglucopyranoside 62 3-xylosyl-24-0acetylhydroshengmanol-15-0-/J-Dglucopyranoside 63 24-O-acetylhydroshengmanol-3-0->3D-xylopyranoside 64 24-ep/-7/?-hydroxy-24-0acetylhydroshengmanol-3-0-/?-Dxylopyranoside 65 24-ep/-24-0-acetyl-7,8didehydroshengmanol-3-0->3-Dgalopyranoside 66 24-ep/-24-0-acetyl-7,8didehydroshengmanol-3-0-/?-Dxylopyranoside 67 24-ep/-24-0-acetyl-7,8didehydroshengmanol-3-O-or-Larabinopyranoside 68 24-ep/-24-0-acetyl-7,8didehydroshengmanol-3-0-(2'-0malonyl)-/?-D-xylopyranoside 69 24-e/?/-24-0-acetylhydroshengmanol3-O-yff-D-galopyranoside 70 cimisideC 71 cimisideD 72 24-O-acetylshengmanol-3-0-/^Dglucopyranosyl-( 1 ->2)-y3-Dxylopyranoside

C 3H oO (842) b

37

n

C H O n (692) e 3 8

6 0

4

7

14

l6

28 C H o0 (842) b

28

C H O (680) g

7

C H O (696) e 12

26

C H O (708) e 12

16

C H 0 , , (678) e

14

C H On(678) e

26

C H O (764) e

27

C H Oi (710) e

16

C H O (842) b C H O (842) b C H O (842) c

29 29 30

43

37

37

38

3 7

37

40

38

7

60

60

60

16

1I

5 8

58

60

62

14

2

43

70

16

43

70

16

43

70

16




Table I. Continued. No. Compound 73 23-0-acetylshengmanol-3-0-yff-Dxylopyranoside 74 23-0-acetyl-7,8didehydroshengmanol-3-0-/?-Dgalopyranoside 75 23-0-acetyl-7,8didehydroshengmanol-3-0-(2'-O malonyl)-/?-D-xylopyranoside 76 23-0-acetyl-shengmanol-3-0-(2'-(> malonyl)-/?-D- xylopyranoside

Ref. Formula (MW) Source 9,17;18, C37H 8O (662) d,e,g 19 14 C38H58On(690)e

77

C 7H56O (660)e

78

79

80 81 82 83 84 85 86 87 88 89 90 91 92

23-0-acetyl-7,8didehydroshengmanol-3-0-j0-Dxylopyranoside 23-acetylshengmanol-3-0-/?-Dglucopyranosyl-( 1 ->3)-/?-Dxylopyranoside 23-0-acetyl-7,8didehydroshengmanol-3-O-cr-Larabinopyranoside 23-0-acetyl-shengmanol-3-0-a-Larabinopyranoside 23-0-acetyl-la-hydroxyshengmanol3-0-/?-D-xylopyranoside 7>0-hydroxy-23-O-acetylshengmanol3-O-^-D-xylopyranoside cimiracemoside L cimiracemoside M cimicifugoside H - l bugbanosideD bugbanosideE cimifiigoside H-5 cimicidanol-3-(9-arabinoside cimicidanol cimicifol (20R,24R)-24,25-epoxy-3/H/34> xylopyranosyloxy)-9,19-cyclolanost7-ene-16,23-dione

5

10

C oH 80,3(746)e

27

C4oH6oO,3(748)e

27

4

5

3

10

27 C43H 0 (824)e

9

C 7H 6O (660)e

16

C37H 8O (662)g

12,7

C3 H 80„(678)e

17

C37H 80n(678)e

31

C39H6oO„(704)g C39H oO (704)g C35H 0 (616) g , h C37H 40„(674)e C37H 4O (658)e C35H 2O (632)h C35H 20 (616) c C oH440 (484) c C37H 4O (658)c C35H O8(600) b

7 7 7,32 13 13 32 32 25 25 33

68

3

15

5

10

5

7

10

5

5

6

52

n

9

5

5

10

5

5

3

I0

9

5

5

52

10


67 Tabic I. Continued. No.

Compound Formula (MW) Source Ref. 33 C H520 (616) b 93 (20R,24R)-24,25-epoxy-15ahydroxy-3 /3-(P-D-xy lopyranosy loxy)9,19-cyclolanost-7-ene-16,23-dione 7,25,3: C 5H54O (634) c, g,h 94 cimicifugoside H-2 35

8


3

95 bugbanosideC 96 15a-hydroxycimicidol-3-0-/?-Dxylbinopyranoside 97 24-hydroxy-12/?-acetoxy-25,26,27trinorcycloart-16,23-dione-3-0-or-Larabinopyranoside 98 cimifugoside H-3 99 dahurinol 100 cimiracemoside E 101 isodahurinol 102 25-O-methylisodahurinol 103 dehydroxydahurinol 104 24-0-acetyHsodahurinol-3-O-/?-Dgalactopyranoside 105 shengmanol xyloside 106 cimiaceroside A 107 cimiaceroside B 108 2'-0-malonyIcimiaceroside B 109 cimiracemoside F 110 cimiracemoside G 111 cimiracemosideH 112 20(S),22(/?),23(5),24(/?)16/?:23 ;22:25-diepoxy-12/?-acetoxy3 #23,24-trihydroxy-9,19cycloanostane-3-O-a-Larabinopyranoside 113 20(S),22(rt),23(S),24(/?)16/?:23;22:25-diepoxy-3A23,24-triol9,19-cycloanostane-3-0-/?-Dglucopyranosy l-( 1 -»2)-/?-Dglucopyranosy l-( 1 ->2)-)0-Dxylopyranoside

l0

C 7H 60 (692)e G 5H 4O (650) c,h

13 25,32

C 4H O (620)b

4

C C C C C C C

0 (576) h O (488) b,c O (662)g O (488) b,c O (502) b,c 60 (470) b , c O„(692)c

34 35,36 21 35,36 35,36 35,36 22

H O (638)a,b,c H540 (618) a,g H O (620) a H O (706)e H 60n(676)g H O (676)g H O (678)g H5 On(678)g

37 19,38 38 27

3

5

12

3

5

n

3

C C C C C C C C

52

H H H H H oH H

32

48

30

48

10

9

5

35

58

30

48

5

31

50

5

3

3 8

35

35

35

4

10

4

6 0

58

10

9

56

38

58

37

5

9

12

3 7

5 6

n

3 7

5 8

n

37

8

C H 0 (944)h 4 7

7 6

1 9

19,21 21 21 12

39



Table I. Continued. Formula (MW) Source No. Compound 114 20(5),22(/?),23(5),24(/?> C57H84O21 h (1120) 16/?:23;22:25-diepoxy-3A23,24-triol9,19-cycloanostane-3 -2)-^D-glucopyranosy l-( 1 ->2)-y0D-xylopyranoside C 2H480 (528) c 115 27-deoxyacteol C37H 60„(676)c 116 acteol-3-O-arabinopyranoside C 7H56O (660) c , g 117 23-e/?/-26-deoxyactein C 5H O (600) g 118 cimiracemoside I C 7H 6O (660)g 119 cimiracemoside N C H54O (658) e , g 120 26-deoxycimicifugoside 3

6


5

3

10

3

52

3

5

8

10

37

121 122 123 124

2'-0-malonylcimicifugoside 2'--gal(p) 19 H /?-D-ga!(p) 20 H /?-D-xyl(p) 21 H /ND-xyl(pM^3)-/?-0-xyl(p) 22 OH /S-D-xyl(p) 23 OH /?-D-xyI(p) 24 H 0-*>-xyl(p) 25 H ar-L-ara(p) 26 H a-L-ara(p) 27 H 0-D-BMP) 28 H a-L-ara(p) (21-CH 0H) 29 H /H>-*yl(p) (21-CH 0H) 30 H a-L-ara(p) 31 H a-L-ara(p) 32 H ^-D-glu(p)-(l-^2)-^-D-xyl(p) 33 H ^-D-glu(p)-Ac £-o-gal(p) =CH or-L-ara(p)7,8-2H CH a-L-ara(p) 12^-OAc =CH ^D-xyl(p)12£-OAc =CH 2

2

54 55 56 57 58 59 60 61 62 63

Ri H H OH H H H H H H H

R< H H H H H H H A 0-o-*yl(p) ar-L-ara(p) H £-D-glu(p) /?-D-glu(p) H £-o-xyl(p) /7-o-xyl(p) OH H Rj H OH 0-D-xy\(p) 0-D-xyl(p) H £-D-xyl(p) OH /?-D-xy!(p) A " ar-L-ara(p) R2 £-D-xyl(p)

Rs Me Me Me H H H Me H H H

2

2

Scheme 1. Structures of compounds identified in black cohosh.


71


OAc

64-72 Ri /J-D-xyl(p) >9-D-gal(p) /J-D-xyl(p) a-L-ara(p) (2-0-malonyl)/?-o-xyl(p) a-L-ara(p) /7-D-xyl(p)

64 65 66 67 68 69 70

71fi-DAy\(p) 0-D-glu(pM^2)/?-D-*yl(p)

72

73-84 R OH

R H H A H A' H A' H A H H H /J-D-glu(p) H /?-D-glu(p) H H 2

3

2

73 74 75 76 77 78 79 80 81 82 83 84

7,8

7 8

7 8

78

87 88 89 90 91 92 93

Ri /J-D-xyl(p) a-L-ara(p) 12j0-OAc cr-L-ara(p) 12/?-OAc /?-D-xy|(p) or-L-ara(p) H ^-D-xyl(p) l2/?-OAc /?-D-xyl(p) ^-D-xyl(p)

99 100 101 102 103 104

1H

A

78

H 7 8

A'

H H OH H H

1

R R.i OH H OH H

94-98

2

H

94 95 96 97 98

H

OH OH OH H

OH H H H

H H

H

R OH (24/?) OAc(24S) OH (245) OH OH OAc(245) 2

R. /7-D-xyl(p) ar-L-ara(p) /?-D-xyl(p) a-L-ara(p) /?-D-xyl(p)

R OH H OH H, 7,8-dihydro OH 2

R H OAc H OAc H 3

R H OH OH H H 4

105 R=v0-D-xyl(p)

99-104 R. H /?-D-xyl(p) OH OH OH /?-D-gal(p)

3

RiO

85-93 85 86

R H

R. R H £-D-xyl(p) H ^-o-gal(p) H (2 -0-mal ony l)/?-D-xy l(p) H (2 -0-malony l)/?-D -xy l(p) H /?-D-xyl(p) ^-D-glu(p)--xyl(p)

R

3

/

(

Phytochemistry and Quality Control of Black Cohosh (Actaea

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