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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5987_Библиотеки_им_академика_М_И_Перельмана.pdf
282
Pharmaceutical Chemistry of Natural Products
O
H
OH
H
Me
H
OMe
H
H
H
OH
Cymarose
O
O
OH
H
H
CHO
OH
HO
Strophanthidin
⫹
HORMONES
Hormones are chemical substances with intense biological activity, produced by certain specialized
cells usually in a ductless gland called endocrine gland in the body and transported through
circulation to exert physiological effect on their target cells. Hormones exert their control by acting
either directly or, more likely, indirectly on the DNA of the genes.
Hormones regulate body functions and maintain homeostasis in the variable external/internal
environment (Table 6.5). The defi ciency of a hormone leads to a particular disease, which can be
cured by the administration of the hormone concerned.
Table 6.5 Some of the hormones and their body functions
Major regulator hormone Body function
Aldosterone, antidiuretic hormone Circulating volume
Glucocorticoids, adrenaline Adoption to stress
Gonadotropins, androgens, oestrogens, progestins Sex and reproduction
Insulin, glucagon Availability of fuel
Thyroxine Metabolic rate
Steroids and Hormones
283
Classification
Hormones are classifi ed as follows:
Steroids Nonsteroids
Sex hormones
Oestrogens Progestins
Male sex hormones
(Androgens)
Female sex hormones
Adrenal cortical
hormones
Hormones
SEX HORMONES
These are a group of steroids biosynthesized in the testes, ovaries, adrenals and placenta during
pregnancy. The activity of these sex hormones is controlled by the hormones that are produced in
the anterior lobe of the pituitary gland.
The sex hormones regulate reproductive functions and sexual processes and are responsible
for the development of secondary male and female sex characteristics.
284
Pharmaceutical Chemistry of Natural Products
Biosynthesis of Sex Steroid Hormones
Figure 6.6 outlines the biosynthesis of sex steroid hormones in the body.
O
HO
Dehydroepiandrosterone
Androstenedione
Estrone
O
Aromatase
O
O
HO
O
Side chain
cleavage
Cholesterol
Pregnenolone
i) 5-Ene-3-beta-hydroxy steroid dehydrogenase
ii) 3-Oxosteroid-4,5-isomerase
HO
17-Alpha-hydroxylase
OH
O
17 -Hydroxy pregnenolone␣
HO
17,20-Lyase
Progesterone
O
O
HO
Figure 6.6 Biosynthesis of sex steroid hormones (Continued)
Steroids and Hormones
285
5 Dihydrotestosterone␣-
H
OH
O
5-Alpha reductase
Testosterone
17 Beta-hydroxy steroid
dehydrogenase
HO
Aromatase
OH
OH
Estradiol
Estradiol dehydrogenase
O
Figure 6.6 Biosynthesis of sex steroid hormones
The sex hormones are classifi ed into three types:
1. Androgens: These are male hormones.
2. Oestrogens: These are female or follicular hormones.
3. Gestogens: These are corpus luteum hormones.
ANDROGENS (MALE SEX HORMONES)
The testes produce mainly one androgen, namely testosterone. It is excreted in the urine as
such or mainly as metabolites like androsterone and dehydroepiandrosterone (DHEA).
Testosterone and its more potent reduction product 5α-dihydrotestosterone (DHT) are
produced in signifi cantly greater amounts in males; however, females also produce these
‘male’ sex hormones in lower amounts. These androgens have two important activities, i.e.
promoting male sex characteristics (androgenic activity) and muscle building activity (anabolic
activity). Androsterone is the most potent, having approximately one-seventh of the activity
of testosterone.
Urine contains approximately 1 mg of androsterone per litre of urine. In 1931, Butenandt
isolated the fi rst male sex hormone, namely androsterone. He had isolated 15 mg of crystalline
androsterone from 15,000 L of urine.
Biological Activities of Androgens
Testosterone and DHT cause masculinizing effects, even in the male fetus. They induce the
development of prostate, penis and related sexual tissues. At the time of puberty, the secretion of
testosterone by the testes increases greatly, leading to an increase in facial and body hair, deepening
of the voice, increased protein anabolic activity and muscle mass, increase in size of sexual organs.
Spermatogenesis begins and the prostate and seminal vesicles increase their activity. The skin
becomes thicker and sebaceous glands increase in number leading to acne in many young people.
The androgens also play important roles in male psychology and behaviour. Testosterone plays a
role in libido, mood, muscle mass and strength, as well as in bone density of women.
286
Pharmaceutical Chemistry of Natural Products
Therapeutic Uses of Anabolic Androgenic Steroids
1. They are mainly used in androgen replacement therapy in men, either at maturity or in
adolescence.
2. They are used in advanced or metastatic breast carcinoma of selected patients.
3. They are also used to relieve bone pain associated with osteoporosis and to treat certain
anaemias.
Following are the testosterone and its synthetic anabolic androgenic steroids:
Testosterone
17 -Methyltestosterone␣
CH
3
CH
3
OH
HH
H
O
CH
3
H
CH
3
OH
HH
O
H
H
H
O
CH
3
CH
3
CH
3
OH
HH
HH
CH
3
O
OH
O
H
H
CH
3
CH
3
CH
3
OH
HO
F
H
HH
H
CH
3
CH
3
CH
3
O
OH
O
Methandrostenolone
(Dianabol)
Fluoxymesterone
Oxandrolone (Oxandrin)
Nandrolone
CH
3
Androgens of Pharmaceutical Importance
Androsterone
O
H
H
H
H
HO
Androsterone
Steroids and Hormones
287
Androsterone occurs in urine as a conjugate with glucuronic acid of male and female animals and
in the testicular extract. This also occurs in blood as sulphate. Small amounts are present in the
adrenal cortex, human sperm and ovary.
To isolate androsterone, urine is concentrated, hydrolysed with acid and extracted with
chloroform. The chloroform layer containing hormone is treated with potassium hydroxide
repeatedly to get rid of all the acidic and phenolic impurities. By steam distillation, the neutral
fraction of the additional quantities of the inactive materials is removed. The steam-distilled
fraction is treated with Girard’s reagent. The Girard derivative is extracted and hydrolysed to yield
the androsterone.
HO
H
H
H
Cholesterol
HO
H
H
H
Cholestanol
H
O
HO
H
H
H
H
Epiandrosterone
O
H
H
H
H
Cholestanone
H –Pt
2
CrO
3
O
HO
H
H
H
H
Androsterone
(i) Reduction in acid
medium
(ii) Ac O (iii) CrO
(iv) Hydrolysis
23
(i) Reduction in neutral
medium
(ii) Ac O (iii) CrO
(iv) Hydrolysis
23
288
Pharmaceutical Chemistry of Natural Products
DHEA
HO
HH
H
Dehydroepiandrosterone
O
In 1935, Butenandt isolated DHEA from urine. The activity of this hormone is from one-third to
one-half of that of androsterone. It is of interest to note that DHEA has also been obtained from
the urine of pregnant and nonpregnant women. Its structure resembled the structure of oestrone
quite markedly.
Cholesterol
Cholesteryl acetate dibromide
HO
H
H
H
AcO
H
H
H
Br
Br
(i) Ac O
(ii) Br
2
2
CrO –AcOH
3
O
AcO
H
H
H
Br
Br
Zn/AcOH
O
AcO
H
H
H
O
HO
H
H
H
Dehydroepiandrosterone
Hydrolysis
Steroids and Hormones
289
Testosterone (Nuvir, Andriol, Testoviron)
1
2
3
5
6
7
8
9
10
11
12
13
14
15
16
17
19
4
18
CH
3
CH
3
OH
H
H
O
H
Testosterone (or) ( )-17-hydroxy-10,13-dimethyl-
1,7,8,10,11,12,13,15,16,17-decahydro-2 -cyclopenta[ ]
phenanthren-3( )-one
8R,9S,10R,13S,14S,17S
H
6H,9H,14H
␣
All steroidal hormones which exhibit a typical androgenic activity are derivatives of androstane.
However, the most potent one is testosterone. Androsterone is the most potent among the other
androgens having approximately one-seventh of the activity of testosterone.
Isolation: In 1935, testosterone was isolated by E. Laqueru et al. from testes. From 100 kg of
testes, they obtained 10 mg of testosterone.
Metabolism of testosterone
O
OH
H
O
O
H
HO
O
H
5 -Dihydrotestosterone␣
O
O
Glucuronate
H
O-Glucuronate
H
HO
HO
OH
H
Androstanediol
Uridine diphospho-
glucuronosyl
transferase
Uridine diphospho-
glucuronosyl
transferase
3 -17-Hydroxy steroid
dehydrogenase (HSD)
a
17 -HSD
5 -Androstanedione␣
3 -HSD␣
Androsterone
Uridine diphospho-
glucuronosyl
transferase
290
Pharmaceutical Chemistry of Natural Products
HO
Testosterone
O
5 -reductase␣
Aromatase
O
Oestradiol
OH
P450
5 reductase␣-
17-Hydroxy steroid
dehydrogenase (HSD)
Androstenedione
O
Glucuronate
HO
O
O
H
glucuronate
3aHSD
5 -Reductase
Etiocholanolone
O
H
O
H
O
Uridine diphospho-
Glucuronosyl transferase
OH
Synthesis
Chloesterol
(i) Ac O
(ii) Br
2
2
HO
Br
Br
CrO
3
⫺
CH COOH
3
CH
3
O
C O
CH
3
O
C O
Br
Br
O
(i) Zn–CH COOH
(ii) Hydrolysis
3
Cholesteryl acetate dibromide
Steroids and Hormones
291
CH
3
O
CO
OH
(i) Ac O
(ii) Na–C H OH
2
25
O
HO
(i) C H COCl
(ii) Mild hydrolysis
(CH OH–NaOH)
65
3
OCOC H
65
HO
Oppenauer oxidation
OCOC H
65
O
Hydrolysis
KOH
Androst-4-ene-3,17-dione
O
O
OH
O
Testosterone
Testosterone cypionate
Dehydroepiandrosterone
Oxidizing agent O
2
O
O
C CH
2
CH
3
CH
2
CH
3
OCOC H
25
O
Testosterone propionate
Testosterone enanthate
CH (CH ) COCl
325
CH CH COCl
22
Pyridine
O
Properties and uses: It is a creamy white crystalline powder, insoluble in water and soluble in alcohol.
It may be used for palliative treatment of breast carcinoma in postmenopausal women.
Assay: Dilute the sample in alcohol to 50 mL with ethyl alcohol. Measure the extinction at the
maximum at about 241 nm using ethyl alcohol in the blank.