Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
272
Pharmaceutical Chemistry of Natural Products
2. Bile acids facilitate digestion of fats by emulsifi cation. The emulsifying process converts fats
which are insoluble in water into water-soluble compounds that can be easily absorbed in
the intestine.
3. They also activate the enzymes cholesterol esterase and pancreatic lipase.
4. They also keep cholesterol in solution.
SAPONINS AND SAPOGENINS
The term saponins is derived from the Latin word sapo which means soap. Saponins are glycosides
characterized by spiroketal side chain and their property of forming foams in water. They are
used for their detergent properties. They exhibit haemolytic action and produce toxic effect when
injected but are harmless when taken orally. Digitalis purpurea was the fi rst source of saponins
to be identifi ed, but it is more important as a cardiac glycoside; richer sources of saponins were
discovered later.
As the saponins are glycosides, upon hydrolysis they give an aglycone (sapogenin), sugars
(D-glucose, D-xylose, L-rhamnose, L-arabinose) and related uronic acids. Aglycones are linked to
sugars by glycosidal linkage at C-3. On the basis of the structure of the aglycone present, saponins
are classifi ed into two types: (i) steroidal (tetracyclic) triterpenoids and (ii) pentacyclic triterpenoids
(structure mentioned below). Steroidal alkaloids are a subgroup of the steroidal saponins, possessing
a heterocyclic nitrogen containing ring that provides the basic property.
A
B
C
1
2
3
4
5
6
7
8
9
10
11
12
19
D
13
15
14
16
17
18
20
21
22
23
24
25
26
27
Pentacyclic triterpenoid skeleton
Steroidal skeleton
A
B
CD
E
CH
3
CH
3
CH
3
H
3
C
Steroidal Saponins
The steroidal saponins are less widely distributed in nature than the pentacyclic triterpenoid type.
Some species of Strophanthus and Digitalis contain both steroidal saponins and cardiac glycosides.
Examples of saponins, source and their constituent sugars are given in Table 6.1.
Steroids and Hormones
273
Table 6.1 Source and sugar components of steroidal saponins
Steroidal saponin Sugar components Occurrence
Dioscin 1 Glucose, 2 rhamnose Dioscorea spp.
Sarsaponin
3 Glucose, 1 rhamnose Smilax spp.
Digitonin 2 Glucose, 2 galactose, 1 xylose Seeds of Digitalis purpurea and Digitalis lanata
Gitonin 1 Glucose, 2 galactose, 1 xylose Seeds and leaves of D. purpurea and seeds of D. lanata
Due to their relationship to compounds such as cortisone, diuretic steroids, sex hormones,
vitamin D and the cardiac glycosides, steroidal saponins have much pharmaceutical importance.
Some of them (especially diosgenin) are used as starting material for the synthesis of the steroidal
compounds. Chemical structure of some steroidal saponins is shown in Figure 6.2.
O
O
A
B
C
D
E
F
HO
3
5
6
Diosgenin
O
O
HO
O
Hecogenin
22 25
O
H
H
b-D-Glu-O
OH
H
H
O-b-D-Glu
H
O
O
O
O
H
OH
H OH
H
HO
H
H
OH
H
H OH
H
Sarsaporilloside
O-ram-L-a
274
Pharmaceutical Chemistry of Natural Products
Dioscin
O
H
H
OH
H
H
H
O
O
H
HO
O
O
H
OH
H
OH
OH
H
H
Me
H
O
O
H
Me
H
OH
H
OH
OH
H
O
H
Me
o
OH
H
H
H
OH
OH
o
H
H
H
OH
Digitogenin Tigogenin
o o
Figure 6.2 Chemical structure of some steroidal saponins
Synthesis of Diosgenin
COOH
R
H
HBr/peroxide
Br(H C)
23
C COOH
Me
H
(i) EtOH/HCl
(ii) LAH/AlCl
3
Br(H C)
23
C CH OH
2
Me
H
Steroids and Hormones
275
HO
O
O
N H /KOH
24
Me
H
OH
MnO
2
(i) AcCl
(ii) NaNO /Urea/DMF
2
Me H
O
ON
2
AcOH C
2
R
H
t-BuOK/
t-BuOH
Diosgenin
HO
H
O
O
Me
H
(i) NaBH /EtOH(0.3 hr)
4
(ii) H
⫹
HO
AcOH C
2
H
NO
2
O
H
Sources of steroidal sapogenins are shown in Table 6.2.
Table 6.2 Sources of steroidal sapogenins
Sapogenin Source
Diosgenin Dioscorea sylvatica, D. mexicana and D. composite
D. collettii, D. pathaica, D. nipponica, D. fl oribunda
Hecogenin Agave sisalana, Hechtia texensis
Sarsapogenin Yucca spp., Smilax spp
Sarmentogenin Strophanthus spp.
276
Pharmaceutical Chemistry of Natural Products
Pentacyclic Triterpenoid Saponins
The pentacyclic triterpenoid saponins are rarely available in families of monocots but are abundant
in many dicot families. Aglycones are linked to sugars or uronic acid units, or both by glycosidal
linkage at C-3 of steroidal glycoside (Table 6.3).
Table 6.3 Pentacyclic triterpenoid saponins and their sugar components
Saponin Genin Sugar components
Calendula saponin A Oleanolic acid 2 Glucose, 1 galactose, 1 glucuronic acid
Glycyrrhizic acid
Glycyrrhetinic acid 2 Glucuronic acid
Guaiacin Noroleanolic acid 1 Rhamnose , 1 glucose, 1 arabinose
Hederacoside A (hederin) Hederagenin 1 Glucose, 1 arabinose
Primula saponin Primulagenin 1 Rhamnose, 1 glucose, 1 galactose, glucuronic acid
Quillaja saponin Quillaic acid
(hydroxygypsogenin)
Glucuronic acid, 6 sugars and acyl moieties
Saikosaponin A Saikogenin F 1 Glucose, 1 fructose
Triterpenoid saponins may be classifi ed into three types: α-amyrin, β-amyrin and lupeol. By
replacing a methyl group by a carboxyl group, the related triterpenoid acids are formed. Some of
the triterpenoid acids are shown in Figure 6.3.
COOH
HO
R'
R''
COOH
H
O
HO
Glycyrrhetinic acid
Oleanolic acid CH H
Hederagenin CH OH H
Gypsogenin CHO H
Quillaic acid CHO OH
3
2
R' R''
Figure 6.3 Triterpenoid acids of saponins
Steroids and Hormones
277
STEROIDAL ALKALOIDS
Steroidal alkaloids arise by the inclusion of basic nitrogen at some point of the steroid molecule,
hence they are also known as azasteroids. The nitrogen present in these compounds provides the
basicity to the molecule. They may be divided into two major groups:
1. Compounds in which N is in the steroid nucleus.
2. Compounds in which N is in one or more side chains.
Structurally the steroid alkaloids (Figure 6.4) may also be classifi ed into four groups based on
the basic carbon skeleton. These are as follows:
1. Pregnane alkaloids: Based on the pregnane framework this name has been derived. These
compounds exhibit remarkable structural diversity (e.g. conessine, funtumine, cyclobuxine
D and pachystermine A).
2. Solanum alkaloids: These are found generally as glycosides and isolated from various species
of the family Solanaceae. They are all C-27 cholestane derivatives and belong to fi ve structural
groups of which the solasodine and solanidine types are the most common.
3. Salamandra alkaloids: These consist of several highly toxic-related substances isolated from
the skin glands of various species of salamander.
4. Veratrum alkaloids: These consist of two distinct C-27 series, designated as jerveratrum and
ceveratrum.
(a) Jerveratrum groups: These contain one to three oxygen atoms and occur as free alkamines
and are also combined as glycosides (e.g. pseudojervine and jervine).
(b) Ceveratrum groups: These contain seven to nine oxygen atoms and occur as ester with
various acids (e.g. germine, protoverine and veracevine).
Me N
2
H
H
H
H
N
Me
Conessine
HO
H
H
H
N
H
Solanidine
Holarrhimine(C)
CHNH
2
CH
2
HO
HC
3
HH
H
HN
2
Holaphylline
HC
3
N
H
CH
3
CO
Veratramine
HO
H
N
H
H
HO
Figure 6.4 Examples of steroidal alkaloids
278
Pharmaceutical Chemistry of Natural Products
CARDIAC STEROIDS OR CARDIOTONIC GLYCOSIDES
These are plant steroidal glycosides used as heart stimulants (cardiotonics) since ancient times,
as they exert action on failing heart and produce slowing and strengthening effect. At lower
doses they slow down and strengthen the heart beat, but in excessive doses they may cause
cardiac arrest. The pharmacological effect of the cardiac glycosides (e.g. digoxin) depends
on both the aglycones and the sugars attached. Although the inherent activity resides in
aglycone, the sugars are responsible for solubility and fi xation of the glycoside to the heart
muscle (Table 6.4).
Table 6.4 Glycone and aglycone portion of some important cardiac glycosides
Glycoside Aglycone Sugar moieties
Digoxin
Digitoxin
Acetyldigitoxin
Lanatoside A
Lanatoside B
Lanatoside C
Acetyldigoxin
Deacetyllanatoside C
Lanatoside D
Lanatoside E
Digoxigenin
Digitoxigenin
Digitoxigenin
Digitoxigenin
Gitoxigenin
Digoxigenin
Digoxigenin
Digoxigenin
Diginatigenin
Gitaloxigenin
(Digitoxose)
3
(Digitoxose)
3–
Acetyldigitoxose–(digitoxose)
2–
Glucose–acetyldigitoxose–(digitoxose)
2–
Glucose–acetyldigitoxose–(digitoxose)
2–
Glucose–acetyldigitoxose–(digitoxose)
2–
Acetyldigitoxose–(digitoxose)
2–
Glucose–(digitoxose)
3–
Glucose–acetyldigitoxose–(digitoxose)
2–
Glucose–acetyldigitoxose–(digitoxose)
2–
O
O
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22
23
A
B
C
D
13
O
OH
OH
(Digitoxose)
3
Digoxin
The sugar units attached to the aglycone by a C-3 β-linkage are comprised of up to four sugar
units which include glucose or rhamnose together with other deoxy sugar units. Examples of deoxy
Steroids and Hormones
279
sugars are 2,6-dideoxyhexoses (e.g. digitoxose) or their 3-O-methyl ethers (e.g. cymarose). The
sugars isolated from the hydrolysis of cardiac glycosides are unique and are not found elsewhere
in nature (Figure 6.5).
CHO
OH
HO
OH
OH
CH OH
2
CHO
OH
OH
OH
CH
2
CH
3
CHO
OH
HO
OH
CH
3
H
3
CO
CHO
OH
HO
OH
OH
CH
3
D-Glucose
D-Digitoxose
D-Digitalose D-Glucomethylose
L-Rhamnose
D-Fructose
L-Thevetose
D-Cymarose
CHO
HO
HO
HO
CH
3
OCH
3
CHO
OH
OH
CH
2
OCH
3
CH
3
CHO
OH
HO
HO
OH
CH
3
CHO
OH
HO
HO
OH
CH
3
Figure 6.5 Sugars of cardiac glycosides
Aglycones present in cardiac steroids may be distinguished according to whether there is a
fi ve- or six-membered lactone ring. These types are known as cardenolides (e.g. digitoxigenin) and
bufanolides or bufadienolides (e.g. scillarenin), respectively, and the following formulae indicate
their structure and ring numbering. The two types may differ in the confi gurations at C-3 and C-5
and also in unsaturation and oxygen functions.
280
Pharmaceutical Chemistry of Natural Products
O
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22 23
Cardenolide
O
O
A
B
C
D
D
13
14
15
16
17
18
20
21
22
23
24
Bufadienolide
1
2
3
4
5
6
7
8
9
10
11
12
19
A
B
C
Cardenolides: Cardenolides are the commonly found type and contain an α,β-unsaturated
γ-lactone ring. These occur mostly in plants, certain genera of Digitalis (especially, D. purpurea) are
the main source of most of the drugs of therapeutic value. Chemical structure of some typical
genins of cardenolides is shown below.
O
O
Digitoxigenin
A
B
D
O
O
Gitoxigenin
A
B
D
O
O
Digoxigenin
A
B
D
O
O
Diginatigenin
A
B
C
D
O
O
Strophanthidin
A
B
D
O
O
Gitaloxigenin
A
B
C
D
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22 23
C
13
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22 2 3
C
13
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22 23
C
13
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22 2 3
13
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
20
21
22
23
C
13
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22
23
13
HO
OH
HO
OH
OH
HO
OH
OCHO
HO
OH
OH
HO
OH
OH
OH
HO
OH
OH
CHO
Bufadienolides or scilladienolides: These contain a δ-lactone ring which has a conjugated diene
system. In plants, they occur in squill family. Chemical structure of some typical genins of
bufadienolides is shown below.
Steroids and Hormones
281
13
O
O
D
14
15
16
17
18
20
21
22 23
24
Scillaridin-A
1
2
3
4
5
6
7
8
9
10
11
12
19
A
B
C
13
O
O
D
14
15
16
17
18
20
21
22 23
24
Hellebrigenin
1
2
3
4
5
6
7
8
9
10
11
12
A
B
C
HO
OH
HO
OH
OH
CHO
Chemical Tests for Identification of Cardiac Glycosides
1. Baljet’s test: A thick section shows yellow to orange colour with sodium picrate.
2. Legal’s test (test for cardenolides): To aqueous or alcoholic extract add 1 mL pyridine and 1 mL
sodium nitroprusside, pink to red colour appears.
3. Test for deoxy sugars (Keller–Kiliani test): To 2 mL of the extract add glacial acetic acid, one
drop of ferric chloride and concentrated sulphuric acid. Reddish brown colour appears at the
junction of the two liquid layers and the upper layer appears bluish green.
4. Liebermann’s test (test for bufadienolides): Mix 3 mL of extract with 3 mL acetic anhydride, heat
and cool the solution; add few drops of concentrated sulphuric acid. Blue colour appears.
Enzymatic or chemical hydrolysis of cardiac glycosides affords the aglycones or genins and one
or more sugars. For example, the enzyme strophanthobiose cleaves k-stropanthoside to cymarin and
two moles of glucose. Acid hydrolysis of cymarin yields strophanthidin and a rare sugar cymarose.
O
O
OH
H
H
CHO
OH
Enzyme
⫺2 Glucose
O
O
OH
H
H
CHO
OH
O-cymarose
Cymarin
H
+
k-Strophanthoside
O-cymarose- -glucoseb - -glucoseb