NI DUNG

Glycosid bao gm: 1. Glycosid tr tim 2. Anthraquinon (Anthraglycosid = Anthranoid)

3. Mono v diglycosid
4. Saponin (saponosid) 5. Flavonoid (flavonosid) 6. Coumarin 7. Tanin (tanoid)

8. Glycosid cyanogenic
2

NI DUNG
I. INH NGHIA II. CU TAO - PHN LOAI Cu tao Phn loai Tn goi III. TINH CHT Ly tinh Hoa tinh IV. CHIT XUT
3

I. INH NGHIA
INH NGHIA RNG
GLYCOSID = NG Dy ni glycosid PHN T HU C

INH NGHIA HEP

GLYCOSID = NG Glucosid*

Dy ni glycosid

KHNG NG

Phn ng: ose, glycon Phn khng phai ng: aglycon, genin

II. CU TAO VA PHN LOAI

1. CU TAO
H O + H2O OH R CH OH + HO-R OR

R C

CH OH

+ HO-R

OR R CH OR

Aldehyd
HO HO HO

Hydrat aldehyd
C H2 O H O OH + H O R

Ban acetal
HO HO HO

Acetal
C H2 O H O OR

ng Glycon

Hu c (A)glycon

Glycosid
5

OH HO O OH OH O OH HO O O ose

OH + ose OH

FLAVONOID

OH

+ ose HO

ose

SAPONOSID

Aglycon

Glycosid
6

OH glucose HO

Me

OH OH O COOH

Anthraquinon

Acid carmicic
HO

HO

HO

Coumarin

umbeliferon

esculetin

Glycosid va pseudoglycosid
HO HO HO C H2 O H O OH + H O R HO HO HO C H2 O H O OR

HO HO HO

C H2 O H O

HO HO R HO

C H2 O H O

O H+ H O OC
OH

O OC R

HO

O O

ga lloyl O
OH glucose rhamnose

CH2O ga lloyl O

ga lloyl O O O ga lloyl
8

OH

meta - triga lloyl

2. PHN LOAI
2.1. Phn loai theo loai dy ni glycosid
GLYCOSID

O glycosid

S glycosid
Thioglycosid = Glucosinolat

C glycosid

N glycosid

ROH + HX R

RX R
9

O-glycosid va C-glycosid
glucose O OH
glucose

HO

OH

Liquiritin

Puerarin

OH
HO

OH

OH

O O
OH O

OH glucose rhamnose

CH2OH glucose

Rutin

Barbaloin
10

S-glycosid va N-glycosid
CH2 CH CH2 C S glucose
HO CH2 C S N O SO3K glucose

N O SO3K

Sinigrin trong Hc gii t

Sinalbin trong Bach gii t

NH2 N N N ribose N

NH2 N O N H N Ose
11

Glycosid trong nucleosid

Glycosid trong Hat Ba au

2. PHN LOAI (tip)

2.2. Tn gi theo cu tao cua phn Aglycon
GLYCOSID Holosid (Glycon + Glycon) Carbohydrat Heterosid (Glycon + Aglycon)
Glycosid tim Saponin Flavonoid Anthraglycosid...
12

3. TN GOI
3.1. Tn goi cac holosid
3.1.1. Tn goi theo s lng ng

ng n (ose)
Disaccharid

Oligosaccharid
Polysaccharid (glycan)

13

3.1. Tn goi cac holosid

3.1.2. Tn goi theo loai ng v cu truc chui ng

- Homopolysacharid (homoglycan)
Glucan, fructan, mannan, araban, xylan...

- Heteropolysaccharid (heteroglycan)
Gm, pectin, cht nhy...
Gluco-mannan, manno-glucan, manno-arabino-glucan, fuco-manno-galactan, galacto-gluco-manno glycan.

- Polysaccharid phc hp
Glycolypid, lipopolysaccharid

Peptidoglycan, proteoglycan, glycoprotein

Glycosaminoglycan
14

3.2. Tn goi cac heterosid

- Tn goi theo ban cht dy ni O-glycosid N-glycosid C-glycosid S-glycosid Pseudo glycosid - Tn goi theo phn aglycon

Flavonosid, saponosid, anthraglycosid, glycosid tim... - Tn goi theo loai ng

Glucosid, manosid, galactosid, rhamnosid - Tn goi theo s lng ng trong mt mach ng Monosid, biosid, triosid - Tn goi theo s lng mach ng trong phn t Monoglycosid (monodesmosid) diglycosid (bidesmosid), triglycosid (tridesmosid)... - Tn ring: IUPAC: ~osid 15

III. TINH CHT CUA GLYCOSID

1. TINH CHT LY HOC

1.1. Trang thai t nhin

Tn tai trong cy: tan trong dich khng bao. Th cht: Cht rn v inh hinh / (kt tinh) Mau: a s khng mau

Anthraglycosid: vang cam n o sm,

Flavonoid: Khng mau - vang nhat o cam o.

Vi: thng co vi ng, glycyrrhizin co vi ngot ...

16

L TNH
1.2. Tinh tan Dang glycosid: Phn cc trung binh manh rt manh.
Cu tao cua aglycon: Khung chinh, M, cac nhom th Cu tao cua phn ng: s mach ng, s ng, loai ng

Tinh tan
Tan / dung mi phn cc (trung binh manh): R-OH, nc, hn hp cn nc, dioxan, AcOH, pyridin... Khng tan / dung mi phn cc trung binh kem.

Dang aglycon:
Tan c trong dung mi phn cc yu (kem phn cc) trung binh: n-hexan, ether du, toluen, benzen, CHCl3, CH2Cl2 Et2O, EtOAc, aceton, R-OH, pyridin, AcOH Khng tan trong nc.
17

2. TINH CHT HOA HOC

2.1. Phan ng thuy phn

Enzym co sn trong thc vt:

Nhe nhng, chon loc hn artefact (artifact) Acid v c (HCl, H2SO4, HClO4 ): O- glycosid < O- acid uronic < C-glycosid a s cac trng hp cn tranh thuy phn (phai n nh dc liu- Cynarin/ actis (artichoke, artichaut ) Mt s trng hp co th ng dng s thuy phn.

- Thuy phn ranuculin cho protoanemonin co tinh khang khun.

- Saponinsteroid/da M (cy tha), thuy phn cho hecogenin - Diosgenin/ mia d, cu mi. - Digitoxin/Digitalis
18

S THUY PHN
O thuy phan bang strophanthobiase C HO b-glucosidase H2SO4 OH OH (aglycon) Strophanthidin Cymarin K-Strophanthosid K-Strophanthosid b g
19

g lc

g lc

cym

S THUY PHN CYNARIN /ACTIS

Oxydase
Oxydase

Esterase

Esterase

Cynarin
(1,3-di-O-caffeoylquinic acid)

20

C C DC

21

S THUY PHN HYOSCYAMIN / CA CDC

Tropic acid

Esterase

Nhom alkaloid
(khng phai glycosid)
22

l-Hyoscyamin

S THUY PHN
LI DNG S THY PHN
Enzyme

Ranunculin

Protoanenomin

23

S THY PHN SAPONIN / DA M, MIA D

Hecogenin

24

CHIT XUT DIOSGENIN

Enzym Diosgenin glucosid

Diosgenin

Dioscin

25

Hoa tinh
2.2. Phan ng cua phn ng Phan ng kh: Chi th hin sau khi a thuy phn Cac phan ng khac: ty thuc vo loai ng. 2.3. Phan ng cua aglycon Ty thuc vo cu truc cua aglycon: Saponin, flavonoid

26

CHIT XUT GLYCOSID

Bt dc liu Loai tap kem phn cc
Chit glycosid bng d. mi phn cc t. binh manh Dich chit Loai dung mi Thuy phn

Glycosid t.phn

Aglycon t.phn Tach aglycon t. khit = k. tinh p. oan, sc ky Aglycon t.khit

27

Tach glycosid tinh khit = k.tinh p. oan, sc ky Glycosid t.khit

CHIT XUT GLYCOSID

Cc phng php chit xut:

PP chit c in:
- Ngm (c hay khng c gia nhit) - Ngm kit (c hay khng c gia nhit) - Hm, sc Chit vi s h tr cua siu m (>20 KHz): thng dng quy m th nghim v dung mi chit c tnh phn cc (to thng hay gia nhit). Chit vi s h tr cua vi sng: Bc xa in t tn s 2450 MHz lm gia nhit nhanh, tng kha nng ha tan ng thi ph huy vch t bo. Chit xut lng (siu) ti han
28

CHIT XUT LNG SIU TI HAN

Chit cht lng (siu) ti han (Super-critical Fluid extraction, SFE): CO2 (31,10c; 73,8 bar). H2O (374,20c; 220,5 bar). EtOH (243,40c; 72 bar).

29

CHIT XUT LNG SIU TI HAN

30

CHIT XUT LNG SIU TI HAN

31

CHIT SOXHLET

32

PHN LP
SC KY CT: - Sc k ct (Columm Chromatography, CC) - Sc k chn khng (Vacuum Chromatography, VC) - Sc k nhanh (Flash Chromatography, FC) - Sc k trao i ion (Ion-exchange Chromatography, IP) - Sc k loai tr phn t (Size-exclusion Chromatography) - Sc k lng p sut trung bnh (MPLC) - Sc k lng cao p (High Pressure Liquid Chromatography, HPLC). - Sc k lng cao p iu ch (Preparative High Pressure Liquid
Chromatography, Prep. HPLC)

- Sc k lng siu ti han (Supercritical Liquid Chromatography,

HPLC).

- Sc k cp ion: (Ion-Pair Chromatography, IPC)

33

PHN LP
2. SC KY PHNG (planar chromatography): pha tnh c c nh trn mt mt phng (giy, ban mng), pha ng di chuyn qua b mt nh mao dn hoc cc lc khc (trng lc, ly tm), bao gm: - Sc k lp mng (Thin Layer Chromatography, TLC) - Sc k lp mng iu ch (Preparative Thin Layer Chromatography, PTLC) - Sc k p sut trn (Over Pressure Liquid Chromatography, OPLC) - Sc k ly tm (Centrifugal Chromatography, CC) - Sc k giy (Paper Chromatography, PC)
34

PHN LP
3. SC K NGC DNG (Countercurrent Chromatography, CCC): - Khai trin phn b ngc dng (Countercurrent Distribution
Development, CDD)

Sc

ngc

dng

git

nh

(Droplet

Countercurrent

Chromatography, DCCC)

- Sc k phn b ly tm (Centrifugal Partition Chromatography, CPC) hay cn c gi l sc k ngc dng ly tm (Centrifugal

Countercurrent Chromatography, CCC).

- Sc k phn b ly tm nhanh (Fast Centrifugal Partition

Chromatography, FCPC).

Sc k ngc dng tc cao (High Speed Countercurrent

Chromatography, DCCC).

Sc

ngc

dng

ra

giai

(Elution

Extrusion

Countercurrent Chromatography, EECCC).

- Sc k ngc dng quay phn vng (Rotation Locular 35

Countercurrent Chromatography, RLCC).

SKLM

36

SKC
1 2 3 4 5 6

F
UV 365

E D C B A

37

SC KY CT CHN KHNG (VACUUM LIQUID CHROMATOGRAPHY, VLC)

B cne cao su

Erlen hng Erlen khng y Ban knh ri

38

SK NGC DNG

39

HSCCC cua hng Analytical Instruments Ltd

40

Thit b FCPC (fast centrifugal partition chromatography)

a). S pha trc cua thit b FCPC: 1. Ct c cc a; 2. Trc ly tm b). Thit k cc knh trong a : 3. Cc knh; 4. ng dn
41

SKLM LY TM

42

Prep. HPLC

43

Prep. HPLC

44

LC-UV-MS-NMR

45

LC-MS-NMR-CD

46

47

NI DUNG
A. AI CNG V GLYCOSID TIM I. INH NGHIA II. LICH S III. CU TRUC HOA HOC IV. TINH CHT V. INH TINH INH LNG VI. PHN B THIN NHIN B. CAC DC LIU CHA GLYCOSID TIM 1. Digitalis 2. Strophanthus 3. Truc o 4. Hnh bin

48

A. AI CNG V GLYCOSID TIM

I. INH NGHIA
Glycosid tr tim = Glycosid b tim = Cardioactive glycosides (Anh) = Glycosides cardiotoniques (Phap) L nhng glycosid steroid co tac dng c bit trn tim Liu iu tr: Manh (Renforcer) Chm (Ralentir) iu ha (Regulariser) Quy tc 3R (Potair) Liu c: Nhanh Rung tim Giam co bop Ngng tim ky tm thu (ch), tm trng (VMN)
49

II. LICH S
1250: Meddygon myddfai (Welsh) Foxglove c dng tr nhc u v co tht. 1542 (1543): Leonhart Fuchs (Trbinghen) Historia Stirpium Digitalis c tc dng nhun trng v li tiu. 1640: Parkinson ngh s dng 1650: London Pharmacopoeia 1744: Edinburgh Pharmacopoeia 1748 (1732): Paris Pharmacopoeia

1754: Wittenberg Pharmacopoeia

50

LICH S (tip)
1785 (1760-1775): William Withering - An account of the foxglove and some of its medical uses: with practical remark on dropsy and other diseases. William Withering (17 March 1741 6 October 1799) was an English botanist, geologist, chemist, physician and the discoverer of digitalis.

Leonhart Fuchs (Trbinghen)

51

LICH S (tip)
1808: Desteuches ln u tin CX hat cht/Digitalis nhng tht bai 1841-1842: Homolle v Quevenne CX cht v nh hnh/Digitalis c hat tnh sinh vt. 1958: Walz Cx 2 glycosid l convallamarin v convallarin/ Convallaria majalis L.

1869: Nativelle cx Digitalin kt tinh.

1873: Fraser cx 1 cht c hat tnh SH, t tn l Strophanthin/ hat cy Strophantus Kombe.

1879: Jarmersted cx Scillarin/Scilla maritima

52

LICH S (tip)
1882: Corvello cx Anonidin/Adonis vernalis 1888: Arno cx Strophanthin v ouabain tinh khit/ Acocanthera ouabaio

Cc nh NC ngi c nh Schmiedeberg, Cloetta, Killiani cx nhiu glycosid tim khc

1915: Windaus v L. Hermans bt u NC cu trc nhng mi n 1933 Jacobs mi NC cu trc mt cch c h thng (ha ging v tng hp). 1934: G.A.R. Kon cng b cu trc aglycon (tia X) Tscheche, Elderfield, Reischtein, NC v cng b cu trc hng loat glycosit tim.
53

III. CU TRUC CA GLYCOSID TIM

Khung steroid
Aglycon

5 canh Vng lacton 6 canh

GT
ng

ng thng thng
ng 2 de(s)oxy ng 2,6 de(s)oxy

54

Cu truc

1. Phn aglycon
1.1. Khung steroid
12 18 17

1 2 3

19

11

A
4

10 5

13 8 14

16 15

B
6

Khung Steran (gonan)

55

Cu truc
1.2. Vng lacton
O O b
17 14
14

O O b
17

OH HO
3

Me HO
3

Cardenolid

Bufadienolid
56

Cu truc 1.3. Cu truc lp th

O O
18

13 12

Lact on OH 17

C / D : cis
14

b
17

cis
R
1 2

19 10

11 9

14

OH HO
3

5 4

A / B : cis

HO
3

A B C D cis trans cis

57

1.4. Mt s aglycon chinh

O O
12 14

O O OH
12 14

OH HO
3

OH HO
3

Digitoxigenin

Digoxigenin

58

Mt s aglycon chinh
O O

14

16

OH

OH HO
O O
3

Gitoxigenin
O O CH

OAc
14 16

14

16

OH HO
3

OH HO
3

Gitaloxigenin

Oleandrigenin
59

O O

O O

14

14

OH HO
3

OH HO
3

OH

R = CH2OH cannogenol

R = CH2OH strophanthidol

R = CHO cannogenin
R = COOH acid cannogenic

R = CHO strophanthidin
R = COOH acid strophanthidic

60

2. Phn ng ng desoxy
D

2 6

ng

ng 6-desoxy

ng 2,6-desoxy

L
61

ng 6-desoxy

6
O

MeO

b-D-Fuc

-D-The

O OMe

L-Rha

L-The

62

ng 2,6-desoxy

2 6

6
O
OMe O

D-Boi

D-Dig

D-Cym

OMe

O OMe

L-Ole

L-Cym
63

3. Glycosid

O O
12

T digitoxigenin (3,14)

digitoxin
OH dig dig dig O
3

O O OH

T digoxigenin

digoxin
OH dig dig dig O
3

(3,12,14)

64

4. Lin quan gia cu truc v tac dng

Structure Activity Relationship, SAR

Khung Steroid
Phan aglycon Vong Lacton

Phn ng

65

Khung Steroid

Thay khung Steroid:

A / B cis trans: C / D trans : nh hng cua OH C3 : nh hng cua OH C14 : Mt OH C14: Thm OH C12 :

Mt tac dng
Giam tac dng (# 10 ln) Mt tac dng , Giam tac dng nhiu , Mt tac dng Mt tac dng Tng tac dng (Digoxin)

phn cc cua aglycon:

Hp thu, chuyn hoa v

thai tr
66

Vng lacton

Bufadiennolid > cardenolid

nh hng cua vng lacton
O O O O

Thay vng Lacton

M vng Lacton Bao ha ni i
OH

OH

67

Phn ng Anh hng chu yu ln s hp thu, tich luy, thai tr

Gn ng vo OH / 19 : it tac dung

n g

O A B

HO

68

IV. TINH CHT CA GLYCOSID TIM 1. Ly tinh

Cht rn, co th kt tinh, khng mu v ng

Tan trong nc, ROH, hn hp cn - nc Tan it / CHCl3 (tan nhiu hn khi it ng, hoc ng b alkyl hoa)

Khng tan /DM kem phn cc (hexan, ether, benz)

69

Ph UV :
Cardenolid: 215 218 nm Bufadienolide: 300nm)
O O

log

215
14

O O b

b
17

4.0 3.0 2.0 1.0

OH HO
3

300
HO
3

17 14

Me

bufadienolid
cardenolid

200

250

300

350 nm

Ph IR : bufadienolide 1540, 1640, 1730 cm1

70

2. HOA TINH
2.1. Phan ng cua dy ni glycosid
D b thuy phn ng desoxy d b thuy phn hn 2.2. Phan ng cua phn aglycon Phan ng cua nhn steroid

Phan ng cua vng lacton

2.3. Phan ng cua phn ng Phan ng cua ng 2-desoxy

71

2.1. Phan ng cua phn ng

2.1.1. Phan ng vi thuc th Xanthydrol ng 2-desoxy + Xanthydrol BM mau o man

Xanthydrol + HCl + AcOH (ng nghim dai + nut bng, nhung / becher nc nong)
- 2,6-desoxy : (+) - Kem nhay vi 2-desoxy a b acetyl hoa - m tinh vi 2-desoxy ni vi glucose (C4) - m tinh vi 6-desoxy

- Ose co OH C5 v C6: ngn can phan ng.

72

Phan ng cua phn ng

2.1.2. Phan ng vi H3PO4 ng 2-desoxy + H3PO4

Aceton Cach thuy

mu vng

2.1.3. Phan ng Keller Kiliani (ng 2-desoxy + Keller-Kiliani

1. FeCl3 / AcOH 2. FeCl3 / H2SO4
73

2.2. PHAN NG MU CA PHN AGLYCON

2.2.1. Khung steroid
- Liebermann Burchard 2.2.2. Vng lacton 5 canh - Phan ng vi kim

- Tattje
- Huynh quang vi H3PO4

- Phan ng vi dn cht nitro

Kedde Baljet

Legal
Raymond - Marthoud

Mi trng acid

Mi trng kim
74

Phan ng Liebermann Burchard Glycosid tim /CHCl3 + (Ac2O)

- Khng c hiu !
- Mu cng ro khi cng it tap cht.

H2SO4

Phan ng Tattje Thuc th Tattje: FeCl3 + H2SO4 + H3PO4 Khung steroid + FeCl3
H3PO4 H2SO4

mu o

c hiu vi khung steroid co OH C16 (gitoxigenin)

75

Phan ng Pesez - Jensens Khung steroid + H3PO4

hydrazin hydrat EtOH

huynh quang/UV
Mu xanh ve
O O

- Phan ng vi khung steroid co OH C16 (gitoxigenin). - Co th dung inh lng

gitoxigenin
HO
3

14

16

OH

OH

76

2.2.2. Phan ng cua vng lacton 5 canh 2.2.1.1. Phan ng vi kim Tao dn cht iso khng cn tac dng
O O O O HO O O HO O O O

OH OH OH

OH OH

Iso glycosid tim

2.2.2.2. Phan ng vi cac dn cht nitro (thm) Tao cac san phm mu dng nh tinh Glycosid tim + nitro (thm)
OH

mu

77

Phan ng Raymond Marthoud

NO2

Glycosid tim +
NO2

NaOH

tim khng bn xanh dng

Phan ng Kedde
NO2

Glycosid tim +
NO2

COOH

NaOH

mu o tia

78

Phan ng Baljet
NO2

Glycosid tim + NO2

NO2

OH

NaOH

mu cam

Phan ng Legal
NaOH

Glycosid tim + Na2{Fe(CN)5}NO

mu o

79

2.2.3. Phan ng cua vng bufadienolid Bufadienolid + SbCl3 / CHCl3

Cach thuy

mu tim

2.2.4. Phan ng khac (Cardenolid va bufadienolid)

Glycosid tim + (H2SO4 + furfurol)

mu khac nhau

80

V. INH TINH INH LNG

1. nh tinh hoa hoc S dng cac phan ng hoa hoc nh tinh 1.1. Chit dc liu Dc liu DL. loai tap DC. cn Cn cn Dc liu DC. Cn loang DC. Loai tap Cn cn loang

DC. CHCl3

DC. CHCl3/ cn

81

V. INH TINH INH LNG

1.2. nh tinh S dng cac phan ng mu nh tinh Cac phan ng cua ng desoxy
Xanthydrol Keller-Kiliani Acid Phosphoric Baljet Legal SbCl3/CHCl3 Kedde Raymond-Marthoud

Cac phan ng cua vng lacton

Cac phan ng cua nhn steroid

Liebermann-Buchard Tattje Pesez - Jensens
82

V. INH TINH INH LNG

2. INH TINH SC KY

1. Sc ky lp mong (si-gel)
CHCl3 MeOH CHCl3 pyridin BAW (9:1) (6:1) (10:1:3) DCM MeOH H2O (80:19:1) EtOAc MeOH H2O (16:1:1) EtOAc pyridin H2O (5:1:4)

2. Sc ky giy
CHCl3 THF Formamid Benz EA Formamid n-BuOH bao ha nc Toluen n-BuOH b.ha nc

Hin mu: TT. Kedde (o); Raymond-Marthoud (tim xanh)

83

V. INH TINH INH LNG

anh gia bng phng phap sinh vt n v meo Liu ti thiu cua dc liu hay cua glycosid tim lam cho tim mo ngng p, tinh theo 1kg th trong. Thi nghim tin hanh trong nhng iu kin qui inh Tim tinh mach ngng tim ky tm trng n v ch (.V.) Liu ti thiu cua dc liu hay cua glycosid tim lam cho a s ch trong 1 l ch thi nghim bi ngng tim. Thi nghim tin hanh trong nhng iu kin qui inh. Tim di da, ngng tim ky tm thu Quy nh trong DVN v nhiu nc. V b cu (USP/NF 1995)
84

V. INH TINH INH LNG

Phng phap khac

PP o quang (phan ng mu) (EP, BP)

Raymond-Marthoud (=540nm) Baljet (=495nm) Xanthydrol (=470nm) Keller-Kiliani (=590nm)

PP sc ky long ap sut cao (HPLC)***

PP min dch phong xa,

PP min dch enzym,

PP min dch huynh quang
85

VI. TAC DNG DC LY CA GLYCOSID TIM

C ch: c ch d lp th enzym Na+K+ ATP-ase (Bm natri) Lm tng nng natri ni bo Lm tng nng calci ni bo Tng cng co c

c ch cholinesterase
Tac dng ln thn kinh ph v Giam nhp tim, chng loan nhp

86

VI. TAC DNG DC LY CA GLYCOSID TIM

GLYCOSID TIM K+ Na+ Trao i Na+-Ca++ Na+ Ca++

Na+-K+ ATPase Si c

Ca++

K+ Na+
CO C c ch > 30% ATP-ase Tac dng tr tim c ch > 60% ATP-ase c, Ca++ cao loan nhp
87

VI. TAC DNG DC LY CA GLYCOSID TIM

Tac dng Trn tim Cung lng tim Tng hiu nng tim Thn kinh ph v Giam dn truyn, giam xung nhp xoang nhi tht Tng trng lc i giao cam ( trng lc giao cam) nhp tim, chng loan nhp, keo di tm trng, time nghi, phc hi nng lng tiu th O2 lm cho bnh nhn d th, nhp h hp tr lai binh thng Mach: Gian tinh, ng mach ngoai vi Giam sc can ngoai vi giam hu ganh Thn Giam aldosteron giam gi Na+ Li tiu,
88

VI. TAC DNG DC LY CA GLYCOSID TIM

Phn nhom Nhom 1 Tng sc co bop, chm nhp tim manh Tac dng chm, keo di, o thai chm tich luy Digitalin, Ac Digitalin Nhom 3 Chu yu l tng sc co bop c tim Tac dng nhanh (tim) o thai nhanh, it tich luy K-strophanthin, ouabain Nhom 2 Tac dng trung gian gia nhom 1 v 3 Digoxin, Ac-Digoxin, desacetyl lanatosid C
89

VI. TAC DNG DC LY CA GLYCOSID TIM

Chi nh Suy tim man Tim cn u mau cung cp Cung lng tim thp Nhp tim nhanh Khng co tr ngai ng tng mau Suy tim cp Loan nhp tim Chng chi nh Ri loan dn truyn tim Tng kich thich nhi tht Yu nut xoang, mach chm Bnh c tim co lp (chen ng tng mau)
90

VI. TAC DNG DC LY CA GLYCOSID TIM

Cach dng Liu tn cng: Co hiu qua tr liu, c Duy tri
Thuc o thai it: co giai oan nghi Thuc o thai nhiu: co th dng lin tc

c tinh Nguyn nhn

Qua liu Giam chuyn hoa Thiu kali huyt

Biu hin
Loan nhp tim Thiu nng thn Ri loan in giai

91

VII. PHN B T NHIN CA GLYCOSID TIM

c tao thnh t Steroid 23C (Lacton 5 canh) v 24C (Lacton 5 canh). Phn b tng i han ch trong 1 s ho thc vt:

Thc vt hat kin, chu yu lp 2 la mm.

Cac ho thng gp: Apocynaceae, Asclepiadaceae, Ranulculaceae , Moraceae,

Scrophulariaceae, Cruciferae, Sterculiaceae,

Euphorbiaceae, Tiliaceaceae, Celastraceae (ho dy gi), Leguminosae (Fabaceae), Liliaceae, Iridaceae Cardenolid thng gp hn so vi bufadienolid Bufadienolid: Liliaceae, Ranulculaceae
92

93

- Digitalis spp. Scrophulariaceae

Chi co # 28 loai
Phn b chu yu chu u

- Cac loai quan trong nht :

Digitalis lanata Ehrh. Digitalis purpurea L.

Glycosid tim quan trong nht:

Digitoxin Gitoxin

Digoxin
94

M ta thc vt Cy thao > 2 nm Gc la co ria, mep la rng ca tron, gn mt di la ni rt ro. Trang : mau tia hoc khac. Ngun gc trng trot Moc hoang / Chu u. Di thc sang Bc My Trng Ha lan va ng u B phn dung La, thu hai nm th 1 va 2
95

D. purpurea

96

Glycosid tim > 0,3%

Nativelle (1868), Kiliani (1891), Stoll (1938), Haack (1956)
O

Purpurea glycosid A Purpurea glycosid B Glucogitaloxin

H
R

: Digitoxigenin
: Gitoxigenin

OH

O-formyl : Gitaloxigenin
OH O glc (dig)3

Digitoxin = digitalin (kt tinh)

digipurpuridase

Gitoxin
Gitaloxin (kem bn, - OOCH)

Digitalin tan trong EtOH > trong CHCl3 > trong nc

97

Saponin
H O

R1

R2

Tigogenin
Gitogenin Digitogenin

H
OH OH

H
H OH

R1
H HO H

R2

trans trans trans

- Saponin quan trong nht: Digitonin (Digitogenin+glc+glc+gal+gal+xyl), kt tua han tan vi cholesterol - Giup glycosid tim tan tt, tng hp thu

Anthraquinon
1-methoxy-2-methyl anthraquinon, 3-methoxy-2-methyl anthraquinon 3-methyl alizarin, 1,4,8-trihydroxy-2-methyl anthraquinon

Flavonoid

98

INH TINH
1. Chit xut
-

Chit bng EtOH loai tap bng chi acetat

- Chit lai bng chloroform 2. nh tinh - Thuc th Keller-Kiliani; xanthydrol - TT. nhn steroid v vng lacton 5 canh 2. nh lng: - Thuy phn, chit bng ete (CHCl3), mt mu + TT. Kedde, mt mu +TT. Tattje (gitoxin). KQ mu 1-KQ

mu 2 = lng digitoxin ( 50%).

- Tt nht l nh lng bng HPLC
99

Tac dng cua la Digital tia

Hp thu: Hp thu tt v kha hon ton qua ng rut Co tac dng sau khi ung khoang 5 gi (max: 9 h), sau tim tinh mach 30 2 gi (max : 4-12 h) Chuyn hoa: Gn kt vi protein huyt tng, gan, thn. Tich luy trong c tim it hn trong gan v thn. Tai hp thu qua rut Thai tr: Sau # 14 ngy (T1/2 = 5-7 ngy), co khi n 20 ngy Cng dng: Chit digitoxin, tr tim, li tiu, giam ph
100

101

M ta thc vt: La hep va dai hn Digital tia Gn di la khng ni ro Hoa ngn hn Digital tia Trang hoa vang n vang nu co nhng m nu m Hoa nhiu lng Ngun gc: ng nam u Trng Ha lan, Ecuador va My B phn dung La, hang ngan tn/nm D. lanata 102

Digitalis lanata Ehrh.

103

THNH PHN HOA HOC Glycosid tim 0.5 1 % glycosid tr tim, vi 5 genin :

lanatosid A lanatosid B lanatosid C lanatosid D lanatosid E Mach ng :

digitoxigenin** gitoxigenin (16 OH) digoxigenin** (12 OH) diginatigenin (12, 16 OH) gitaloxigenin (16 OOCH) digt digt Ac-digt glc

- Ac (lanatosid A, B, C, D, E)=Deacetyl lanatosid (A, B, C, D, E) - Gluc: Ac (digitoxin, gitoxin, digoxin, diginatin, gitaloxin) - Gluc; - Ac: Digitoxin, gitoxin, digoxin, diginatin, gitaloxin
(Lanatosidase=digilanidase) - glucose
[Ca(OH)2; K2CO3/MeOH]: - Ac

Saponin, anthraglycosid, flavonoid

104

TAC DNG DC LY - c tinh : gp 4 ln la D. purpurea lm chm nhp tim kem hn digitalin

- Tac dng : nhanh hn digitoxin (digitalin)

li tiu ro hn
- Thai tr : nhanh hn digitalin it tich luy hn digitalin

- Cng dng: chit digoxin, digitoxin, lanatosid C,

lanatosid ton phn (digilanid) kt tinh, bao gm lanatosid A, B, C vi t l (46:17:37)%.

105

Cac loai Strophanthus

Strophanthus spp. Apocynaceae Strophanthus gratus Baill. Strophanthus kombe Oliv. Strophanthus hispidus DC. Strophanthus divaricatus Hook. Sng d hoa vang

Strophanthus caudatus Kurtz. Sng d hoa o

106

Strophanthus aambe Strophanthus alterniflorus Strophanthus amboensis Strophanthus annamensis Strophanthus arboreus Strophanthus arnoldianus Strophanthus aurantiacus Strophanthus barteri Strophanthus bequaertii Strophanthus boivinni Strophanthus brevicaudatus Strophanthus bullenianus Strophanthus capensis Strophanthus caudatus (tropical Asia) Strophanthus chinensis (southern China, Vietnam) Strophanthus congoensis Strophanthus courmontii Strophanthus thallone Strophanthus vanderijstii

Strophanthus cumingii Strophanthus dichotomus Strophanthus divaricatus (southern China; { Vietnam) Strophanthus eminii (east Africa; poison: estrophanthin) Strophanthus glabra Strophanthus gratus (tropical west Africa; poison: ouabain, g-strophanthin) Strophanthus hispidus (Togo, Cameroon) Strophanthus laurifolinus Strophanthus kombe (east Africa; poison: kstrophanthin) Strophanthus nicholsoni Strophanthus petersianus (tropical Africa) Strophanthus preussii (tropical west Africa) Strophanthus sarmentosus (tropical Africa) Strophanthus scandens (Mallacca) Strophanthus speciosus (South Africa) Strophanthus welwitschii
107

S. gratus

108

S. gratus

109

Strophanthus kombe Oliv.

110

S. kombe
111

Strophanthus kombe Oliv. Details of record no: 21711

112

Strophanthus kombe Oliv.

113

S. hispidus

114

THANH PHN HOA HOC

Hoat cht : Glycosid tr tim / nhn hat

Strophanthus gratus Strophanthus kombe

G - strophanthin K - strophanthin

Strophanthus hispidus

H - strophanthin

115

S. gratus
O O
19

HO HO
1

OH
11

Hardy v Galois phn lp Gstrophanthin 1877

Trc o Arnaut a phn lp/ Acocanthera ouabaio.

14

HO

OH OH

Ouabain: Khng tan trong CHCl3, ether, tan trong cn, nc nong, it tan /nc lanh.

G-strophanthin = Ouabain= (Ouabagenin) + Rhamnose*** (3 7% trong hat)

116

Strophanthus kombe
K-strophanthin (5 -8%), hu truyn: - K-strophanthin (chu yu) - K-strophanthin - K-strophanthin C HO
Tan/EtOH, nc nong. Ko tan/ether, CHCl3
O O

g lc

g lc

cym

OH OH (aglycon) Strophanthidin

K-Strophanthosid = Cymarin

K-Strophanthosid K-Strophanthosid

b g
117

S. hispidus
H- strophanthin = cymarin = strophanthidin + D-cym Cymarol = strophanthidol + D-cym Periplocymarin = Periplogenin + D-cym
O O O O

OH HO OH cymarose O OH

OH

periplogenin

periplocymarin

118

nh tinh phn bit

1. Vi thuc th Xanthydrol, Keller-Kiliani - ouabain: m tinh - strophanthin: dng tinh 2. Vi acid sulfuric - strophanthin xanh la m - ouabain hng o thm

3. Vi acid phosphoric

- strophanthin
- ouabain - strophanthin - ouabain

huynh quang vng huynh quang vng cam xanh la m nu o

4. Vi (SbCl3 + CHCl3)
5. Nng sut quay cc: - strophanthin: quay phai
- Ouabain: quay trai
119

Chuyn hoa cua ouabain

- Gn nh khng hp thu qua ng tiu hoa
- Qua chu ky gan mt rt it (# 5%) - Khng b chuyn hoa gan - IV : rt mau co tac dng - thai tr:

qua nc tiu (37%, nguyn dang)

qua phn (25%, a chuyn hoa)

120

Tac dng
Tac dng ln tim theo quy tc 3R Chu yu lm tng co bop c tim Tac dng chm nhp tim kem hn digitalin

Ouabain :

hp thu ng rut kem hn nhiu so vi digitalin khi tim: mau co tac dng, mau chuyn hoa (ht tac dng) c gp 2 K-strophantin c gp 10 digitalin

K-strophanthin : dng nh Ouabain (it c hn Ouabain) c: K-strophanthin <K-strophanthin <K-strophanthin

121

Cng dng
Chu yu s dng S. gratus S. kombe Ouabain K-strophanthin

S. hispidus t dng
1 s loi Strophanthus khc i khi cung c dng

122

Strophanthus divaricatus
Sng d hoa vang 9-16% glycosid tim / hat Divaricosid = D-strophanthin* = Sarmentogenin** + oleandrose Tac dng tng t nh v = 2/3 K-strophanthin

Divazid (D. Trung Quc 1963)

-* D-strophanthin l hn hp 3 cht do Vin DL chit v t tn -**Sarmentogenin = 3,14 (-OH), 12(-OH)

S. divaricatus 123

S. divaricatus

124

Sng d hoa o = Sng tru

(Strophanthus caudatus)

S. caudatus
125

S. caudatus

126

TRUC O Nerium oleander L.,

Nerium odorum Soland.,

Ho Apocynaceae

127

128

129

130

131

Truc ao
1. M ta thc vt
- Cy co nha mu trong
- La vong 3, gn phu song song - Hoa: trang n / kep, hng o, hng, trng. - Qua: 2 ai - Hat : chum lng xam

132

2. Vi hoc

Phng n khng
133

134

THNH PHN HOA HOC

La cha 0,5 % glycosid tr tim (17 cht khac nhau) Oleandrin (0.08 0,15 %) Cac glycosid chinh Desacetyl oleandrin Neriantin (+++) thiu OH / C14

Adynerin (+)

Oleandrin = Neriolin = Oleandrosid = folinerin

135

L5 OAc

L5

OH

OH O Oleandrose O Oleandrose

OH

Oleandrin = Neriolin
L5

Desacetyl oleandrin
L5

OH
O Glucose O Digi nose

Neriantin

Adynerin
136

THNH PHN HOA HOC KHAC CHIT XUT

Trong dch chit nc, ngoi glycosid tr tim cn co:
- Polysaccharid - Protein Chit xut: - Chit bng EtOH 25%, loai tap bng Pb(CH3COO)2, loai Pb(CH3COO)2 tha bng Na2SO4. C, lanh c glycosid tim th. Kt tinh lai trong cn 70%. - Chit xut lng siu ti han: Chit vi CO2 lng siu ti han 280 bar, 500C c 5% EtOH thu c oleandrin (0,91%) 137

TAC DNG CNG DNG

Oleandrin: 40.000 VE, 3600 4.000 VM;

Desacethyloleandrin: 6.000 VE
Oleandrin co tac dung nhanh, 20 30 n vai gi
Lam chm nhip tim, keo dai ky tm trng Thai tr nhanh, it tich luy / c th
Oleandrin

Hep van 2 la

D i thuc (ngay sau)

cung co tac dng chng tng san t bo ung th ty ngi.

AnvirzenTM: ch phm l dch chit la truc o co cha 5

polysaccharid, 5 protein v 2 glycosid tim, lm tng kha nng min dch v co hoat tinh cao trn nhiu dng t bo ung th ngi.
138

Hnh bin hoa trng Urgenea maritima L. = Scilla maritima, Liliaceae M ta thc vt:
Thn hnh ln (2 kg hay hn) Hoa trng

Phn b:
Cy cua vng a trung hai

B phn dng:
Hnh, thu hi vo ma he

139

140

141

142

143

Thnh phn hoa hoc

Glycosid tim nhm bufadienlolid Scilaren A Cc glycosid tim khc
Scillarenin O O

OH O
Penicillium enzym Strophantobiase

Rhamnose Proscillaridin

glucose

glucose

2/3 glycosid total

Scillaren A Glucoscillaren A
144

Tac dng dc ly
iu tr suy tim
Hp thu nhanh Tc dng nhanh It tch luy c ng tim (IV) ch = 2 ln ng ung.

Tc dng li tiu ro
Proscilaridin cn c th l tc nhn chng ung th manh, IC50 = 6 7,6 nM

145

Thng thin (Thevetia peruviana L. Apocynaceae)

146

147

Thng thin
Thevetia peruviana (Pers.) K.Schum. Apocynaceae
B phn dng: hat

Thnh phn ho hc chnh:

Thevetin = thevetin A + thevetin B (1:1) Thevetin A: Canogenin + thevetose + gluc + gluc Thevetin B: Digitoxigenin + thevetose + gluc + gluc D tan trong nc, hp thu nhanh, thai tr nhanh It c hn ouabain v digitalin
148

ay qua dai Corchorus olitorius L. Tiliaceae ay qua tron Corchorus capsularis L. Tiliaceae

149

ay qua dai Corchorus olitorius L. Tiliaceae

Olitorisid = strophanthidin + boivinose + glucose Erymosid = strophanthidin + digitoxose + glucose Corchorosid A=Digitoxigenin+ boivinose+glucose Tac dng ging nh k-strophanthin, khng tich lu

iu ch acetyl strophanthidin

150

151

CH PHM
Hoat cht Digitoxin Digitoxin hn hp Acetyl digitoxin Gitaloxin Digoxin Desacetyl lanatosid C (Deslanoside) Strophanthin G Proscillaridin Bit dc (Labo) Digitaline Nativelle (Nativelle) Cardinatine Nativelle (Nativelle) Acylanide (Sandoz) Cristaloxine (Pharmuka) Digoxine Nativelle (Nativelle) Cedilanide (Sandoz) Ouabaine Arnaud (Nativelle) Talusin (Biosedra) ung tim Dc liu

+
+

D.p + D.l
D.p + D.l

+
+

D.p + D.l
D.p + D.l

+
+

D. lanata
D. lanata

+
+

S. gratus
C. maritima
152

153