Pharmacognosy 生藥學

Steroids (類固醇)

School of Pharmacy Hsun-Shuo Chang

藥學系張訓碩

第一教學大樓7樓 藥用植物學科室 (N724)

07-3121101 ext. 2664
hschang@kmu.edu.tw
1
 Aim of study
◆ Introduction of Steroids
◆ Classification of Steroids

• Robbers JE, Speedie MK, Tyler VE. Pharmacognosy and Pharmacobiotechnology. Williams
& Wilkins, Baltimore, 1996.
• W. C. Evans. Trease and Evans Pharmacognosy. 15th edition, W. B. Saunders, London, 2002.
• W. C. Evans. Trease and Evans Pharmacognosy. 16th edition, W. B. Saunders, London, 2009.
• Concise Traditional Chinese Herbal Medicine, 2nd Edition. The Pharmaceutical Society of
Taiwan Pharmacognosy group, Taipei, 2019. 2
 Steroids
◆ a natural product class of compounds that is widely
distributed throughout nature
◆ the diversity of biologic activities of steroids includes:
▬ the development and control of the reproductive tract in
humans: estradiol, progesterone, testosterone
▬ the molting of insects: ecdysone
▬ induction of sexual reproduction in aquatic fungi:
antheridiol

3
 Steroids
◆ wide range of therapeutic applications:
▬ cardiotonics: digitoxin
▬ vitamin D precursors: ergosterol
▬ oral contraceptive agents: semisynthetic estrogens and
progestins
▬ anti-inflammatory agents: corticosteroids
▬ anabolic agents: androgens

4
 Nomenclature
◆ a cyclopentanoperhydrophenanthrene nucleus
◆ chemical nomenclature: based on this fundamental
carbocycle with adjacent side-chain carbon atoms
◆ if one or more of the carbon atoms shown in the structure of
cholesterol is not present, the numbering of the remainder is
undisturbed 22 2421 26

18 20 23 25
12 17
11 16 27
19 13
C D
1
2 9 14 15
10 8
3 A B
5 7
HO 4 6
cholesterol
5
Estrane Androstane Pregnane
O O

Cholane Cholestane Cardanolide

O O

Ergostane Stigmastane Bufanolide

Fig. 7-1. Principal steroid stereoparent hydrocarbons 6
 Nomenclature
◆ an atom or group attached to a ring:
▬ α (broken lines): if it lies below the plane of the paper
▬ β (solid lines): if it lies above the plane of the paper
▬ whose configuration is not known are denoted by wavy
lines and designated ξ (xi) in the chemical name
 R

 
H

H H
 

Fig. 7-2. Orientation of steroid substituents 7

 Nomenclature
◆ the configuration of hydrogen or a substituent at the ring-
junction position is always designated by adding α or β
after the numeral
◆ this numeral and letter are placed immediately before the
stem name
 R
17

  13
H
9 ( 8β, 9α, 10β, 13β, 14α)
14
10 8
H H
 

Fig. 7-2. Orientation of steroid substituents 8

 Nomenclature
◆ in most steroids, rings B and C and rings C and D are fused
trans, whereas ring A and B may be fused either cis or
trans

CH3 CH3
CH3 H R CH3 H 13
R
13

10 C D 17 10 C D 17
9 9
B 8
14
A B 8
14
H 5 5
H H H H
A
H

5 5
(A/B cis; B/C trans; C/D trans) (A/B trans; B/C trans; C/D trans)

9
 Nomenclature
◆ in most steroids, rings B and C and rings C and D are fused
trans, whereas ring A and B may be fused either cis or
trans
21
COOH O
OH
17
H
12
17 13
13 H
H 9
9 14
14 10 8
10 8 H H
3 5
H H
3 5
HO
HO 7 OH H
H

Cholic acid Androsterone

(A/B cis; B/C trans; C/D trans) (A/B trans; B/C trans; C/D trans)
3α,7α,12α-Trihydroxy-5β-cholan-24-oic acid 3α-Hydroxy-5α-androstan-17-one
10
 Nomenclature
◆ an exception on ring fusion: cardanolide or bufanolide
▬ the 14β-configuration as well as the 20R-configuration are
implied in the name

Digitoxin
(A/B cis; B/C trans; C/D cis)
3β-O-Tridigitoxosyl-digitoxigenin
11
 Nomenclature
◆ an exception on ring fusion: cardanolide or bufanolide
▬ the 14β-configuration as well as the 20R-configuration are
implied in the name O

20

OCOCH3

COOH O O 14
H H OH
H2N N
N 6 O
H H
NH
Bufotoxin
(A/B cis; B/C trans; C/D cis)
Bufotalin 3-suberoylarginine ester 12
 O
O O O
CoA SH S CoA
CH3 COOH
S CoA S CoA
Acetate Acetyl-CoA Acetoacetyl-CoA
O

S CoA
HMG-CoA reductase
O OH O OH NADPH2 O OH O
ATP

HO O P HO OH HO S CoA

5-Phosphomevalonic acid Mevalonic acid β-Hydroxy-β-methylglutaryl-CoA

(HMG-CoA)
ATP

O O
P ATP

O PP O PP
HO O PP
3-Isopentenylpyrophosphate (IPP) 3,3- Dimethylallylpyrophosphate (DMAPP)
5-Pyrophospho-3-phosphomevalonic acid

Isopentenyl

pyrophosphate O PP
O PP
Farnesyl pyrophosphate Geranyl pyrophosphate
13
Fig. 7-3. Biosynthesis of cholesterol (Acetate-Mevalonic acid pathway)
 NADPH2
O PP
Farnesyl pyrophosphate
Farnesyl pyrophosphate Squalene

20 squalene epoxidase
H H
17
19 13
9 14
lanosterol cyclase
10 8

HO
H
3
Carbonium ion intermediate 2
H O Oxidosqualene
cycloartenol cyclase lanosterol synthase
24

25

HO
HO H HO
H
Cycloartenol Lanosterol Cholesterol

Fig. 7-3. Biosynthesis of cholesterol 14

Biochem. J. 2004; 378:15889–98
 Cholesterol Biosynthesis Inhibitors
◆ Mevastatin (Compactin)
▬ fungi Penicillium citrinum and P. brevicompactum
▬ ((3S)-3-hydroxyl-3-methyl-glytaryl-CoA) HMG-CoA
reductase inhibitor: the rate-limiting enzyme in endogenous
cholesterol biosynthesis
↓LDL cholesterol levels,
HO O
▬
β-hydroxy-δ-lactone
↓cardiovascular diseases O
O

(coronary heart disease O ethylene bridge

H
and stroke)
hexahydronaphthalene ring

Mevastatin

16
 Cholesterol Biosynthesis Inhibitors
◆ Lovastatin (Mevinolin)
▬ fungi Aspergillus terreus (Aspergillaceae)
▬ 6-methyl group → enhances the in vitro HMG-CoA
reductase-inhibiting activity
HO O
3',5'-dihydroxyheptanoic acid
O
O OH
O

O
hydrolyzed O
H OH OH O
H
in vivo
Lovastatin 6
Mevinolinic acid

NH2 OH O O
HO
H H
N N N
N O S OH
O OH
O
N P P OH O O
N O O 3-hydroxy-3-methylglutaryl
O

HO O
HO
P O HMG-CoA 17
HO
 Cholesterol Biosynthesis Inhibitors
◆ Pravastatin: prepared by microbial transformation using
Streptomyces carbophilus
▬ 6β-hydroxy → hydrophilic than lovastatin
▬ the 3',5'-dihydroxyheptanoic acid active form
HO O

O
O O
OH

O O
H H OH OH O

HO

Lovastatin Pravastatin
18
 Cholesterol Biosynthesis Inhibitors
◆ Simvastatin
▬ (2''-methyl group) → 2.5 times of that exhibited by
lovastatin HO O
HO O

O
O O
O

2''
O O
H H

Lovastatin Simvastatin

◆ Lovastatin, simvastatin, and pravastatin are all widely used in

the treatment of hypercholesterolemia
19
 Steroids
◆ the first steroids from nature were C27-C29 alcohols that
were found in the lipid fractions of many tissues
◆ these compounds were solids and therefore named sterols
from the Greek stereos, meaning solid
◆ the most widely occurring sterol is cholesterol:
▬ first isolated from human gallstones
▬ a constituent of animal cell membranes
▬ found in all animal tissue
▬ one of the chief constituents of lanolin
▬ found in many drug products
20
 Ergosterol (Provitamin D2)
◆ the principal sterol in fungi is ergosterol
◆ this C28 sterol arises biosynthetically through a
transmethylation reaction of the cholestane side chain
involving S-adenosyl methionine
◆ upon ultraviolet irradiation, a series of isomerizations with
the subsequent opening of ring B results in the formation of
vitamin D2 28

UV
H
H

H
H
HO
HO
Ergosterol (Provitamin D2)
Vitamin D2 (Ergocalciferol)
(22E)-Ergosta-5,7,22-trien-3β-ol 21
7-Dehydrocholesterol (Provitamin D3)
◆ Vitamin D3 is formed in the same manner from 7-dehydro-
cholesterol
◆ this compound occurs in small amounts with cholesterol in
animal tissue, including human skin, where irradiation from
the sun catalyzes the formation of vitamin D3

H UV H

H H
HO HO

7-Dehydrocholesterol Vitamin D3
(Provitamin D3) (Cholecalciferol)
Cholesta-5,7-dien-3β-ol 22
 β-sitosterol & stigmasterol
◆ β-sitosterol:
▬ a second transmethylation from methionine for the C-29 atom
▬ from wheat germ oil, rye gem oil, corn oil, cottonseed oil, and
other seed oils 28
29

◆ stigmasterol:
▬ first isolated from calabar H
-Sitosterol
beans but is also found in H
Stigmast-5-en-3β-ol
soybean oil HO

▬ the double bond at position 22 22

of stigmasterol allows it to be
more readily converted into the H

Stigmaterol
pregnane-type steroid HO
H
(22E)-Stigmasta-5,22-dien-3β-ol

hormones than is β-sitosterol 23

 Vitamin D
◆ metabolites of Vitamin D are essential for the absorption
and utilization of calcium
◆ vitamin D3 (Cholecalciferol):
▬ the primary form of the vitamin in zoologic species
▬ stored in the liver and skin
▬ fish liver oils are a rich natural source of this material
◆ vitamin D2 (Ergocalciferol)
▬ derived from ergosterol, a plant steroid
▬ the form of this vitamin normally used to fortify such
foods as milk, bread, and cereals
24
 Vitamin D
◆ called the sunshine vitamin since ultraviolet light is
involved in the conversion of provitamin substances to
vitamins D2 and D3
◆ if the irradiation process is not adequately controlled,
vitamin D2 becomes contaminated with undesirable
reaction products, including lumisterol, tachysterol,
toxisterol, and suprasterols
◆ undergo metabolic hydroxylations in the body to yield
molecular forms with greater physiologic activity

25
 H H

H Vitamin D3
H Vitamin D2
(Cholecalciferol)
HO (Ergocalciferol)
HO

liver

25

OH OH

H
H

H
H

HO
calcifediol HO
25-hydroxyergocalciferol
kidney

OH
OH
OH
OH H
H
1
H
H calcitriol HO
HO 1,25-dihydroxyergocalciferol 26
 Dihydrotachysterol
◆ prepared by synthetic reduction of a tachysterol closely
related to ergocalciferol (vitamin D2) and possesses useful
vitamin D activity
◆ undergoes hydroxylation in the liver to give an active 25-
hydroxyl metabolite; no kidney metabolism occurs or is
required for full activity

25
H
OH
reduction liver
H
H
H

H
H
HO HO
OH
Tachysterol Dihydrotachysterol 27
 Vitamin D
◆ absorbed readily from the small intestine
◆ cholecalciferol (vitamin D3) is absorbed with somewhat
greater efficiency than ergocalciferol (vitamin D2)
◆ bile salts are required for absorption of the latter material
◆ aids in the utilization of calcium and phosphate and is
essential to the development and maintenance of strong
teeth and bones
◆ deficiency states lead to rickets in children and
osteomalacia in adults

28
 Vitamin D
◆ also used to treat familial hypophosphatemia and
hypoparathyroidism and to supplement the diet in
therapeutic regimens involving long-term use of
cholestyramine or anticonvulsant drugs
◆ calcitriol has special utility in patients with kidney failure
◆ chronic vitamin D-induced hypercalcemia may result in
soft-tissue calcification, including lethal vascular
calcification and nephrocalcinosis
◆ common symptoms may include gastrointestinal
disturbances and hypertension
29
 Bile acids
◆ bile acids: the side chain of cholesterol is degraded to C24
steroids, which possess a C-24 carboxyl (in the liver; bile)
H 3C COOH
OH H 3C COOH
CH3 H OH
CH3 H

CH3 H 7α-deoxygenation CH3 H

H H
by intestinal microflora H H
HO OH
H HO
H

Cholic acid Deoxycholic acid (not formed in the liver)

3α,7α,12α-Trihydroxy-5β-cholan-24-oic acid 3α,12α-Trihydroxy-5β-cholan-24-oic acid

H3C COOH H3C COOH

CH3 H CH3 H

CH3 H 7α-deoxygenation CH3 H

H H by intestinal microflora H H

HO OH HO
H H
Chenodeoxycholic acid Lithocholic acid (not formed in the liver)
3α,7α-Dihydroxy-5β-cholan-24-oic acid 3α-Hydroxy-5β-cholan-24-oic acid 30
 Bile acids
◆ is attributed to enterohepatic circulation
◆ generally, the bile acids do not exist in the free state but are
conjugated through a peptide bond to either glycine or
taurine
◆ the conjugated bile acids are discharged into the duodenum
where they act as emulsifying agents to aid in the intestinal
absorption of fat
◆ chenodeoxycholic acid and ursodeoxycholic acid is used in
chronic liver disease such as primary biliary cirrhosis

31
 Chenodiol (chenodeoxycholic acid)
◆ increases the proportion of chenodiol in the bile acid pool,
biliary cholesterol saturation is reduced, and uncalcified
cholesterol gallstones undergo gradual dissolution
(cholelitholytic effect)

◆ Chenodiol has no effect on radiopaque (calcified)

gallstones or on bile pigment gallstones

◆ adverse effects: dose-related hepatotoxicity has been

observed in the formation of lithocholic acid or directly
from chenodiol

32
 Ursodiol (ursodeoxycholic acid)
◆ in small quantities in normal human bile and in large
quantities in the bile of certain species of bears
◆ an epimer of chenodiol having a 7β-hydroxyl rather than a
7α-hydroxyl as in chenodiol
◆ decreased formation of lithocholic acid because the 7-
dehydroxylation reaction by the intestinal microbial flora
appears to be α-specific HC COOH
3

CH3 H

◆ therefore, ursodiol presents a CH3 H

decreased risk of hepatotoxiciy H H

HO 7 OH
H
Ursodiol (Ursodeoxycholic acid)
33
 Cardiac glycosides
◆ some steroids present in nature are characterized by the
highly specific and powerful action that they exert on the
cardiac muscle
◆ these steroids occur as glycosides with sugars attached at
the 3-position of the steroid nucleus
◆ because of their action on the heart muscle, they are named
cardiac glycosides

34
 Cardiac glycosides 9,10,13,16

cardenolide (C23) bufadienolide (C24)

Bufo. (The prototype compound bufalin was
isolated from the skin of toads)

α,β-unsaturated doubly unsaturated

5-membered lactone ring 6-membered lactone ring

cis cis

Digitoxigenin Scillarenin
3β,14-dihydroxy-5β-car-20(22)-enolide 3β,14-dihydroxy-bufa-4,20,22-trienolide 35
 Cardiac glycosides 2

◆ optimum cardiac activity

α,β unsaturated g-lactone ring

17

3 14

cis

cis

Digitoxin
(A/B cis; B/C trans; C/D cis)
3β-O-Tridigitoxosyl-digitoxigenin
36
 Cardiac glycosides
◆ Metabolic reduction

Digoxin
(active)

Dihydrodigoxin
(inactive)

37
 Cardiac glycosides
◆ metabolism

more hydroxyl groups ↑, the more rapid the

onset of action and the subsequent dissipation

1. the molecule solubility properties important Digitoxigenin

in its absorption and distribution in the body (active)
2. the stereochemistry and conformation
influence the binding affinity to a sugar-
binding site on the receptor protein
38
 Digitoxigenin, R1 = R2 = H
(3β,14-dihydroxy-5β-car-20(22)-enolide) 1

Gitoxigenin, R1 = H, R2 = OH
(3β,14,16β-trihydroxy-5β-car-20(22)-enolide)
Gitaloxigenin, R1 = H, R2 = CHO
(16β-formyloxy-3β ,14-dihydroxy-5β-car-20(22)-enolide)
Digoxigenin, R1 = OH, R2 = H
(3β,12β,14-trihydroxy-5β-car-20(22)-enolide)

Ouabagenin Scillarenin
1β,3β,5,11α,14,19-hexahydroxy-5β-car-20(22)-enolide 3β,14-dihydroxy-bufa-4,20,22-trienolide

Fig. Structural formulas of several aglycones of cardiac glycosides. 39

 Digitalis (Foxglove) 12

◆ dried leaf of Digitalis purpurea L.毛地黃(Scrophulariaceae)

◆ indigenous to central and southern Europe and naturalized
in various parts of Europe and in the northern and western
United States and Canada
◆ the leaves of other Digitalis species, D. dubia, D.
ferruginea, D. grandiflora, D. lanata, D. lutea, D.
mertonensis, D. nervosa, D. subalpine, and D. thapsi, also
show the presence of cardiac glycosides
◆ the drug contains a large number of glycosides, of which
the most important from a medicinal viewpoint are
digitoxin, gitoxin, and gitaloxin 40
 Digitalis (Foxglove) 15

◆ the major glycosides, in terms of concentration, include

purpurea glycoside A, purpurea glycoside B, glucogitaloxin,
glucodigitoxigenin-bis-digitoxisides, glucogitaloxigenin-bis-
digitoxiside, glucoevatromonoside, glucogitoroside,
glucolanadoxin, digitalinum verum, glucoverodoxin,
stropeside, and verodoxin
◆ in monitoring patient therapy with digitoxin and digoxin,
radioimmune assay techniques have been developed that
allow for the measurement of nanogram quantities of these
glycosides in the blood serum

41
 Digitoxin 19

◆ D. purpurea, D. lanata, and other suitable species of Digitalis

◆ a white or pale buff, odorless, microcrystalline powder
◆ a bitter substance, insoluble in water and slightly soluble in
alcohol

digitoxose
(2,6-Dideoxy-β-D-ribo-hexopyranose)

3β-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-
ribo-hexo-pyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexo-pyranosyl)oxy]-
14-hydroxy-5β-card-20(22)-enolide 42
 Digitoxin
◆ upon oral administration, the onset of action is 1 to 4 hours
with a peak at 8 to 14 hours
◆ approximately 50 to 70 % of the glycoside is converted by
the liver to inactive genins, which are excreted in the
kidneys
◆ because of a long plasma half-life (168 to 192 hours), it may
take from 3 to 5 weeks for complete dissipation of the drug
from the body following discontinuation of therapy
◆ drug-serum level of 14 to 26 ng/ml is required for full
therapeutic effect, and levels exceeding 35 ng/ml may
produce symptoms of toxicity
43
 Digitalis Lanata (Grecian Foxglove) 3,7

◆ the dried leaves of Digitalis lanata Ehrhart 長葉毛地黃

(Scrophulariaceae)
◆ indigenous to southern and central Europe
◆ the source of digoxin
◆ nearly 70 different glycosides have detected in the leaves of D.
lanata.
◆ five different aglycones: :
▬ digitoxigenin, gitoxigenin, and gitaloxigenin
(also in D. purpurea)
▬ digoxigenin and diginatigenin (only in D. lanata)
44
 Digitalis Lanata (Grecian Foxglove)
◆ the five types of primary glycosides are designated
lanatosides A-E (digilanids), according to the identity of the
aglycone
◆ glycosides derived from aglycones of the C and D series may
be obtained only from D. lanata.

lanatoside A, R = digitoxigenin
lanatoside B, R = gitoxigenin
lanatoside C, R = digoxigenin
lanatoside D, R = diginatigenin
lanatoside E, R = gitaloxigenin

45
Digitalis Lanata (Grecian Foxglove) 4

lanatoside A

alkali, glucosidase

digitoxin

46
 Digoxin (Lanoxin)
◆ the leaves of D. lanata (Scrophulariaceae)
◆ a white, crystalline powder
◆ digoxin tablets are 60 to 80% absorbed
◆ approximately 10 – 40 % of patients of orally administered
digoxin is converted by the intestinal microflora to the
inactive dihydrodigoxin
◆ a solution-filled capsule is available that provides a 90-
100 % absorption, and with enhanced bioavailability
bacterial inactivation is decreased

47
 Digoxin (Lanoxin)
◆ upon oral administration, the onset of action is 30
minutes to 2 hours, with a peak at 2 to 6 hours
◆ digoxin is also administered parenterally for a more
rapid effect
◆ the major route of elimination is the kidneys, and with a
plasma half-life of 30 to 40 hours, complete dissipation
of effects following discontinuation of therapy takes
from 6 to 8 days
◆ drug-serum level of 0.5 to 2 ng/ml is required for full
therapeutic effect, and levels exceeding 2.5 ng/ml may
produce symptoms of toxicity 48
 Other Cardioactive Drugs
◆ Convallaria of lily-of-the-valley root :
▬ dried rhizome and roots of Convallaria majalis L. (Liliaceae)
▬ major: convallatoxin: K-strophanthin (strophanthidin) and
the sugar of G-strophanthin (rhamnose)
▬ minor: convallatoxol and convalloside
◆ Apocynum, black Indian hemp, dog bane, or Canadian hemp:
▬ the dried rhizome and roots of Apocynum cannabinum L.
(Apocynaceae)
▬ cymarin (major), apocannoside, and cyanocanoside

49
 Other Cardioactive Drugs
◆ Adonis or pheasant’s eye :
▬ dried overground portion of Adonis vernalis L. (Ranunculaceae)
▬ adonitoxin, cymarin, and K-strophanthin
◆ Black hellebore or Christmas rose:
▬ the dried rhizome and roots of Helleborus niger L. (Ranunculaceae)
▬ hellebrin
▬ black hellebore possesses cardiac stimulant properties in
contrast to green hellebore, which is a cardiac depressant
◆ Oleander:
▬ the leaves of Nerium oleander L. (Apocynaceae)
▬ oleandrin, a 3-glycosido-16-acetyl derivative of gitoxigenin 50
 Strophanthus 6

◆ the dried, ripe seed of Strophanthus kombe Oliver, or of S.

hispidus DeCandolle (Apocynaceae), that is deprived of the awn
◆ strophanthus seeds have long been used by native Africans in the
preparation of arrow poisons
◆ a mixture of these glycosides (next page), existing in the seed in
concentrations of up to 5 %, was formerly designated
strophanthin or K-strophanthin
◆ ouabain (G-strophanthin) is a glycoside of ouabagenin and
rhamnose
▬ the seeds of Strophanthus gratus (Wall et Hook.) Baillon or
from the wood of Acokanthera ouabaio Poiss. (Apocynaceae) 51
 Strophanthus 14

cymarose

strophanthobiase

-glucose

strophanthidin

α-glucosidase cymarin

-glucose K-strophanthin-β

K-strophanthoside
52
 Squill (Squill bulb) 8,18

◆ the cut and dried, fleshy, inner scales of the bulb of

▬ the white variety of Urginea maritime (Linne) Baker.
(white or Mediterranean squill) (Liliaceae)
▬ U. indica Kunth, (Indian squill) (Liliaceae)
◆ scillaren A (major):
scillarenin (a bufadienolide) + rhamnose + glucose
◆ glucoscillaren A: scillarenin + rhamnose + glucose + glucose
◆ proscillaridin A: scillarenin + rhamnose
◆ expectorant, emetic, cardiotonic, and diuretic properties
53
 Red squill
◆ the bulb or bulb scales of the red variety of U. maritima
◆ use as a rat poison
◆ not be present in the medicinal squill
◆ rodents lack the vomiting reflex, which makes red squill
particularly lethal to these animals
◆ the inadvertent ingestion by humans of plant materials
that contain cardiac glycosides induces the vomiting
reflex and reduces the life-threatening aspects of the
toxic manifestations

54
 Steroid hormones
◆ sex hormones: produced primarily in the gonads and
mediate the growth, development, maintenance, and the
function of the reproductive tract and accessory sex organs
▬ female: estrogens and progestins
▬ male: androgens
◆ adrenocortical hormones: produced by the outer cortical
portion of the adrenal glands
▬ mineralocorticoids: affect the excretion of fluid and
electrolytes, with a subsequent sodium retention
▬ glucocorticoids: affect intermediary metabolism
55
 Hypothalamus

Feedback Releasing factor

Regulation

Anterior Pituitary

Tropic hormone

Adrenal Cortex or Gonads

Steriod hormone

Target Tissue

Fig. 7-4. Regulation of steroid hormone production. 56

 Steroid hormones
◆ prolonged therapy with corticosteroids may cause
irreversible atrophy of the adrenal cortex
◆ high corticosteroid level in the body suppresses the
hypothalamus from secreting the corticotrophin-releasing
factor (CRF) which, in turn, suppresses release of
corticotropin (ACTH)
◆ the amount of ACTH secreted at anytime is influenced by
the integration of CRF stimulation on the anterior pituitary
and negative feedback from circulating corticosteroids
◆ the lack of stimulatory impact of ACTH results in atrophy
of the adrenal cortex 57
 OH
H3C
CH3 CH3
CH3 CH3
CH3 O
CH3
CH 3 CH3 OH
CH3
CH3 CH3
NADPH, O2 CH3

desmolase
HO HO HO

Cholesterol 20,22-Dihydroxy Cholesterol Pregnenolone

H3C oxidase
CH2OH OH CH2OH
CH3 O
CH3 O O
O CH
11β-hydroxylase HO 18 hydroxylase
CH3
21 hydroxylase

O
Progesterone Corticosterone Aldosterone
H3C CH2OH
17α-hydroxylase 17α-hydroxylase CH2OH
CH3 O
CH3 O
OH
CH3 O
11β-hydroxylase O OH
CH3 HO OH
21 hydroxylase

O
Hydrocortisone Cortisone
17α-Hydroxyprogesterone OH
OH
O CH3 CH3
17, 20-desmolase CH3

CH3
CH3

O HO
O
Androstenedione Testosterone Estradiol 58
Fig. 7-5 Biosynthesis and bioconversion of steroid hormones
 59
http://en.wikipedia.org/wiki/Steroid_hormone
 Commercial Production of Steroids
◆ the principal source of the steroid chemical nucleus used in
the drug industry is the plant kingdom
◆ Russell E. Marker:
▬ discovery of a commercially feasible conversion of
steroidal sapogenins to progesterone
▬ 1943, isolated diosgenin from D. macrostachya (D.
Mexicana)
◆ Merck Company:
▬ 1944, successfully produced 15 mg of cortisone from 1 kg
of deoxycholic acid, utilizing 36 separate chemical steps
60
 O

O H3C
H3C
CH3 H 3C O
CH3 CH3
O Ac2O CH3
O
CH3
Pyridine-HCl CH3

HO
H3COCO

Diosgenin Pseudodiosgenin Acetate

O
H 3C
O
H3C
CH3
CH 3 O
H3C

CH 3 O
C O
CH3
O HOAc
CH3

H3COCO
H3COCO

Diosone Acetate Pregnadienolone Acetate

H3C
O H3C
CH 3
CH3 O

CH3
CH3
KOH CrO3

H3COCO

O Progesterone
Pregnenolone Acetate
Fig. 7-6 The Marker Degradation 61
 Commercial Production of Steroids
◆ Upjohn Company:
▬ 1952, found a microorganism, Rhizopus arrhizus, that
could convert progesterone to 11α-hydroxyprogesterone in
an 80 to 90 % yield
CH3
CH3
C O
C O CH3
CH3 HO

11 Rhizopus arrhizus CH3

CH3

also species of
Aspergillus, Dactylium and
Cephalothecium O
O

Progesterone 11α-Hydroxyprogesterone

62
 Steroid hormones
◆ relatively inexpensive starting materials, such as
stigmasterol from soybeans, hecogenin from the sisal
industry, or diosgenin from Dioscorea species, are now
CH 3
employed C O
CH3

11
CH3
chemical

Stigmasterol O
HO
CH3
CH3 fermenters
C O
C O CH3
CH3 HO
OH
O

CH3 chemical CH3

O Cortisone O
11α-Hydroxyprogesterone 63
 CH2OH CH2OH

C O C O
CH3 CH3
OH HO OH
Streptomyces fradiae or
CH3 CH3
Cunninghamella
blakesleeana

O O

Cortexolone Cortisol

CH2OH CH2OH

C O C O
CH3 CH3
R OH R OH

CH3 Corynebacterium simplex CH3

or
Fusarium sp.

O O
Cortisone (R = O) Prednisone (R = O)
Cortisol (R = OH) Prednisolone (R = OH)
64
Fig. 7-7 Microbiologic transformation in production of glucocorticoids.
 CH2OH
CH2OH
C O
CH3 C O
HO OH CH3
HO OH
CH3 Streptomyces sp. OH
CH3

F
F
O
O
9α -Fluorocortisol 16α-Hydroxy-9α-Fluorocortisol

Mycobacterium sp. Corynebacterium sp.

CH2OH
CH2OH
C O
CH3 C O
HO OH Streptomyces sp. CH3
HO OH
CH3 OH
CH3

F
F
O
O
9α -Fluoroprednisolone Triamcinolone
65
Fig. 7-8 Microbiologic transformation in production of glucocorticoids
 Adrenal Cortex

Adrenocorticosteroids Adrenal androgens

Glucocorticoids Mineralocorticoids

Cortisone Aldosterone
Hydrocortisone Desoxycorticosterone

66
 Cortisone
◆ 17,21-dihydroxypregn-4-ene-3,11,20-trione
◆ the acetate ester of this hormone is used intramuscularly,
orally, and topically to treat a wide variety of situations,
such as rheumatoid arthritis, other collagen diseases,
Addison’s disease, and certain allergic and asthmatic
conditions CH3

C O
◆ an appreciable sodium-retaining O
CH3
OH

property can be a major problem CH3 H

with the systemic use of cortisone

H H

cortisone
67
 Hydorcortisone (Cortisol)
◆ 11β,17,21-trihydroxypregn-4-ene-3,20-dione
◆ this hormone and its acetate ester are used intramuscularly,
orally, and topically for the same purposes as cortisone
acetate
◆ intra-articular, intralesional, or soft tissue injection of
cortisol always involves the acetate ester CH3

C O
◆ hydrocortisone sodium phosphate HO
CH3
OH

and hydrocortisone sodium succinate CH3 H

are water-soluble and are used in H H

parenteral formulations when O

intravenous administration is indicated Cortisol

68
 Gonads
◆ the ovaries and testes are exocrine (ova, sperm) as well as
endocrine (hormonal) in function
◆ follicle-stimulating hormone (FSH) leads to the development
of the ovarian follicles, to their formation of ova and of
estrogen, and to the development of the testes and the
maturation of the spermatozoa
◆ luteinizing hormone (LH) is necessary to the development of
the corpora lutea in the ovarian follicles after ovulation, to
the formation of progesterone by the corpora lutea, and to
the production of androgen in the matured testis

69
 Gonads
◆ Androgens (male hormones) and estrogens (female follicular
hormones) act to:
▬ develop and maintain the secondary characters of sex
▬ depress anterior pituitary function, leading in turn to the
depression of the testis or the ovary
◆ Progesterone (corpus luteum hormone) similarly
depresses anterior pituitary function and presents a
mixed antagonism-synergism with estrogenic activity

70
 Testosterone
7β-hydroxyandrost-4-en-3-one (male hormone)
OH
◆ CH3

◆ 17-hydroxyl function of testosterone is CH3 H

oxidized and metabolized to less H H

physiologically active keto compound O
Testosterone
◆ used bucally, implanted subcutaneously, applied transdermally,
or injected intramuscularly (not administered orally)
◆ the cypionate, ethanthate, and propionate esters of the 17-
hydorxyl group, which are characterized by delayed
absorption and destruction
◆ a methyl substituent at C-17 has been used to circumvent the
chemical and metabolic instability of testosterone 71
 Estrogens
◆ Estradiol:
▬ stra-1,3,5(10)-triene-3,17β-diol
▬ used orally, injected intramuscularly, applied
transdermally, and implanted subcutaneously
◆ Estrone:
▬ estra-1,3,5(10)-trien-3-ol-17-one
▬ used intramuscularly OH O
CH3 CH3

H H

H H H H

HO HO
Estradiol Estrone 72
 Premarin
◆ the designation conjugated estrogens (Premarin): estrogenic
substances must contain not less than 50 % and not more than
62 % of sodium estrone sulfate and not less than 20 % and not
more than 35% of sodium equilin sulfate
◆ equilin is estra-1,3,5(10),7-tetraen-3-ol-17-one and is one of
the estrogens that appears in the stage of pregnancy advances;
equilin is only slightly less potent than estradiol
◆ conjugated estrogens may be administered orally or
parenterally, and a progestin may be added concurrently or
sequentially

73
 Progesterone
CH3
◆ pregn-4-ene-3,20-dione
C O
CH3
◆ a number of synthetic progestins
CH 3 H
have been developed that have such
H H
advantages over progesterone as fewer O
side effects when administrated over Progesterone

prolonged periods, oral efficacy, and greater potency

◆ such compounds as hydroxyprogesterone caproate in oil,
medroxyprogesterone acetate (Provera), and
norethindrone (Norlutin) may be used as therapeutic
substitutes for the natural hormone

74
 Summary
◆ Biosynthesis of cholesterol

◆ Cholesterol Biosynthesis Inhibitors

◆ Ergosterol, 7-Dehydrocholesterol, Vitamin D,

Dihydrotachysterol, β-sitosterol & stigmasterol,
Dihydrotachysterol, Bile acids, Chenodiol, Ursodiol

◆ Steroid hormones: Cortisone, Cortisol, Testosterone,

Estradiol, Estrone, Premarin, Progesterone

75
 國考題
1. 下列強心苷的苷元，何者所含羥基（-OH）最多? (104/2)
(A) Digitoxigenin (B) Digoxigenin (C) Strophanthidin (D) Ouabagenin

2. Digitoxigenin四環骨架之C-17接有何種環狀基團? (104/2)
(A) Unsaturated gamma-lactone (B) Unsaturated delta-lactone
(C) Saturated delta-lactone (D) Saturated gamma-lactone

3. 下列何種生藥之主成分為digoxin? (105/2)
(A) Digitalis purpurea (B) Digitalis lanata (C) Digitalis thapsi (D) Digitalis ferrugine

4. Lanatoside A經過鹼、葡萄糖水解酶處理後得到的是：(105/7)
(A) digitoxin (B) digitoxigenin (C) digoxin (D) digoxigenin

5. 下列生藥成分何者非半合成類固醇藥物之原料? (106/2)
(A) diosgenin (B) sitosterol (C) gitogenin (D) platycodigenin

6. 主含哇巴因（ouabain）的生藥屬於何科? (107/2)
(A) Rosaceae (B) Scrophulariaceae (C) Apocynaceae (D) Liliaceae
76
 國考題
7. 毛地黃和長葉毛地黃的比較，何者錯誤? (107/7)
(A)兩者皆具有強心苷成分 (B)共有的苷元（aglycone）為digitoxigenin
(C)前者為藥用digoxin的來源 (D)後者又稱作grecian foxglove

8. 下列何種生藥含bufadienolide類強心苷? (107/7)
(A) digitalis (B) white squill (C) convallaria (D) strophanthus

9. 下列有關bufadienolides的敘述，何者錯誤? (108/2)
(A)分離自蟾蜍（toads）的內臟 (B)六員內酯環位在C-17上
(C)屬於24個碳之強心配醣體 (D)具固醇類架構

10. 下列何種天然物成分可來自動物性生藥? (108/2)

(A) bufadienolides (B) citric acid (C) digitoxin (D) ergotamine

11. Cardiac glycosides常見於下列何科別植物? (108/2)

(A)菊科 (B)錦葵科 (C)夾竹桃科 (D)繖形科

77
 國考題
12. 毛地黃（Digitalis purpurea）不含下列何種強心苷? (108/7)
(A) digitoxin (B) gitoxin (C) gitaloxin (D) digoxin

13. 強心配醣體（cardiac glycosides）之不飽和內酯環（lactone ring）係接在那一位置之碳上?

(109/2) (A) 15 (B) 16 (C) 17 (D) 18

14. K-strophanthin-β經strophanthobiase 水解後，其產物為何? (109/7)

(A) cymarin＋glucose (B) cyamrin＋cymarose
(C) strophanthidin＋cymarose (D) strophanthidin＋glucose

15. Digoxin 在血液中之含量，用下列何種方式檢測之靈敏度可達毫微克（ng）層次? (109/7)

(A) radioimmune assay (B) NMR technique (C) IR technique (D) fluorescence assay

16. 下列有關強心配醣體（cardiac glycoside）基本骨架之敘述，何者錯誤? (110/2)

(A) C-3位上OH為β-型式 (B) lactone ring取代在C-17上
(C) C-14位上之OH為α-型式 (D) A/B/C/D四個環連接方式為cis-trans-cis

17. 下列生藥之活性成分，何者不屬強心苷(cardiac glycoside)? (110/7)

(A) strophanthus (B) centella (C) squill (D) convallaria 78
 國考題
18. 下列強心苷之苷元（aglycon），何者屬於bufadienolide架構? (111/2)
(A) ouabain (B) scillaren A (C) K-strophanthoside (D) digitoxin

19. Digitoxin經過水解後可產生之醣類為下列何者? (111/7)

(A) 6-deoxy-D-glucopyranose (B) 2,6-dideoxy-β-D-ribo-hexopyranose
(C) 2,6-dideoxy-3-O-methyl-ribo-hexose (D) 6-deoxy-L-mannopyranose

79