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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5709_Библиотеки_им_академика_М_И_Перельмана.pdf
292
Pharmaceutical Chemistry of Natural Products
Methyl testosterone
OH
O
CH
3
Synthesis
Dehydroepiandrosterone
HO
O
CH MgI
3
HO
Oppenauer oxidation
OH
CH
3
CH
3
Methyltestosterone
OH
O
Fluoxymesterone (Halotestin)
O
F
HO
OH
CH
3
Synthesis
CH
3
OH
O
17-Methyl testosterone
Aspergillus
(i) -Toluene sulphonic acid
(ii) OH
p
⫺
CH
3
OH
HO
O
O
CH
3
OH
HO
2
CH CONHBr
3
Steroids and Hormones
293
Fluoxymesterone
O
HO
OH
CH
3
HF
OH
O
O
C H ONa
25
O
Br
CH
3
CH
3
F
OH
HO
Properties and uses: It exits as white crystalline powder and is insoluble in water. It is primarily
used for the treatment of androgen defi ciency in men.
Illegal anabolic steroids: Some of the steroids are designed for their high muscle building effects.
These agents are used for increasing the performance in athletics and sports. Following are the
illegally used anabolic steroids:
OH
Desoxymethyltesterone
(DHT)
OH
Tetrahydrogestrinone
(THG)
OH
Trenbolone
O
OH
Gestrinone
O
O
SAR of Androgens
2
3
4
5
10
1
6
7
8
9
11
12
13
14
15
16
17
18
19
CH
3
CH
3
OH
O
Testosterone
A
B
C
D
294
Pharmaceutical Chemistry of Natural Products
Conversion of testosterone to DHT has little effect or may increase potency. Changing the A/B
trans-stereochemistry of known androgens such as androsterone and DHT to the A/B cis-derivative
3β-hydroxy-5β-androstane-17-one and 17β-hydroxy-5β-androstan-3-one, respectively, reduces
both the anabolic and androgenic properties drastically.
O
H
HO
Androsterone
O
H
HO
H
O
OH
H
O
3 -Hydroxy-5 -androstane-17-one
OH
5 -Dihydro testosterone␣
17 -Hydroxy-5 -androstane-3-one
1. These observations indicated the importance of the A/B trans-ring juncture for activity.
2. Oxygen function at C-3 can be removed from testosterone with little reduction in androgenic
activity; however, removal of the –OH group from C-17 sharply reduced the androgenic
activity.
3. The position of the oxygen atom is important. The substitution of oxygen at C-2 affords the
most active compound and the order of activity is 2 > 3 > 4.
4. The relative androgenicity of the olefi ns of 3-deoxy testosterones is in the order of Δ
1
> Δ
2
>
Δ
3
> Δ
4
. But the Δ
2
-isomer displayed the greatest anabolic activity.
5. Wolff and co-workers (considering the fact that sulphur is bioisosteric with CH=CH) have
synthesized the thia, seleno and tellurio androstanes, which displayed androgenic activity.
6. Esterifi cation of testosterone prolonged the activity signifi cantly when it was administered
parenterally. Long-chain aliphatic or arylaliphatic acids such as propionic, heptanoic
(enanthoic), decanoic, cyclopentylpropionic (cypionic) and or β-phenylpropionic acid are
used for the esterifi cation of testosterone.
7. Placement of a 9α and an 11β-OH substituents (analogous to synthetic glucocorticoids) gives
fl uoxymesterone (9α-F-11β,17β-dihydroxy-17-α-methylandrost-4-en-3-one), which is an
orally active androgen showing approximately four times the oral activity than that of 17α-
methyl testosterone.
Steroids and Hormones
295
Fluoxymesterone
CH
3
OH
HO
O
F
8. Fluoxymesterone indicated an anabolic potency 11 times than that of the unhalogenated
derivative.
9. Introduction of double bond at C-14 enhances the androgenicity.
10. The 17β-hydroxyl group is essential for androgenic and anabolic activity. Esterifi cation of
the 17β-hydroxyl group not only enhanced but also prolonged the anabolic and androgenic
properties in some cases.
11. C-17α methylation conferred oral activity on testosterone, whereas increasing the chain
length beyond methyl invariably led to a decrease in activity.
OESTROGENS
Oestrogens are classifi ed as organic compounds that control the uterine cycle. Oestradiol is the
major oestrogen secreted by the ovary. It is synthesized in the Graafi an follicles, corpus luteum and
placenta from cholesterol. Oestradiol provides the greatest oestrogenic activity, with less activity
for oestrone and the least activity for oestriol.
Oestradiol is rapidly oxidized in the liver to oestrone which is hydroxylated to form oestriol.
All the three are found in blood, but oestradiol is the most potent oestrogen. Small quantity (2–20
µg/day) of oestradiol is synthesized in human males also. In male, large quantity of equilin is
produced which has one-fi fth oestrogenic potency of oestradiol.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
17
18
15
HO
O
Oestrogen or 3-Hydroxy-13-methyl-7,8,9,11,12,13,15,16-
octahydro-6 -cyclopenta[a]phenanthren-17(14 )-oneH H
296
Pharmaceutical Chemistry of Natural Products
Isolation of Oestrogens
The oestrogens occur in combination with glucuronic acid. Hence, the material is hydrolysed with
concentrated HCl to get free hormones which are then extracted by organic solvents. The extracts
are then reacted with Girard’s reagent either T or P (trimethylaminoacetohydrazide hydrochloride
[(CH
3
)
3
N
+
CH
2
CONHNH
2
] Cl
–
) to form water-soluble semicarbazone. After separating, the
semicarbazones they are hydrolysed with HCl to regenerate the ketonic hormones.
Ketonic hormone
H
O
⫹ [(CH ) N CH CONHNH ]Cl
33 2 2
⫹⫺
C H OH–CH COOH
25 3
HCl
[(CH ) N CH CONH N ]
33 2
⫹
Cl
⫺
Girard-T
Girard derivative (Semicarbazone)
H
HCl
O
H
Ketonic hormone
Biological Activities of Oestrogens
The oestrogens and, to a lesser extent, progesterone are largely responsible for the development
of secondary sex characteristics in women at puberty, in addition to the important role in the
menstrual cycle. The oestrogens also cause a proliferation of the breast ductile system and
progesterone stimulates development of the alveolar system. The oestrogens also stimulate the
development of lipid and other tissues which contribute to the breast shape and function. Fluid
retention in the breasts during the later stages of the menstrual cycle is a common effect of the
oestrogens.
Steroids and Hormones
297
Metabolism of Oestrogens (Figure 6.7)
HO
Oestrogen
R O Oestrone⫽
Oestrogen 2/4-hydroxylase
Oestrogen 2/4-hydroxylase
2-Hydroxyoestrogen
COMT
(Catechol
O-methyltransferase)
HO
HO
R
R
R
R
HCO
3
HO
2-Methoxyoestrogen
R
OCH
3
HO
4-Hydroxyoestrogen
OH
HO
COMT
4-Methoxyoestrogen
Figure 6.7 Metabolism of oestrogen
Therapeutic Uses of Oestrogens
Oestrogens are used therapeutically as follows:
1. A major use of oestrogens is for the inhibition of ovulation, in combination with progestins
(birth control).
298
Pharmaceutical Chemistry of Natural Products
2. Another major use of oestrogens is in hormone replacement therapy for postmenopausal
women.
3. It is used in the treatment of advanced, inoperable breast cancer (in men and postmenopausal
women) and prostate cancer (in men).
Classification of Oestrogens
Oestrogens are classifi ed as follows:
1. Steroidal oestrogens and their derivatives
Oestradiol
Mestranol
Sodium17 Dihydroequilin- sulphate
Oestrone
Ethinyl oestradiol
HH
⫹⫺
Na O
S
O
O
O
CH
3
OH
HH
⫹⫺
Na O
S
O
O
O
CH
3
OH
Sodium17 -dihydroequilin sulphate␣
Oestriol
HO
CH
3
OH
H
H
H
HO
HH
H
CH
3
O
HO
CH
3
OH
OH
H
H
H
Sodium oestrone sulphate
HH
H
MeO
CH
3
OH
CCH
H
H
H
CH
3
OH
CCH
HO
H
H
H
CH
3
O
⫹⫺
Na O
S
O
O
O
Steroids and Hormones
299
HH
H
⫹⫺
Na O
S
O
O
O
CH
3
OH
Sodium17 -oestradiol sulphate
H
⫹⫺
Na O
S
O
O
O
OH
CH
3
Sodium17 -dihydroequilenin sulphate
HH
H
⫹⫺
Na O
S
O
O
O
CH
3
OH
Sodium17 -oestradiol␣ sulphate
H
⫹⫺
Na O
S
O
O
O
CH
3
OH
Sodium17 −dihydroequilenin␣ sulphate
2. Nonsteroidal or synthetic oestrogens or artifi cial hormones
HO
Benzestrol
C
H
Et
OH
Hexoestrol
C
H
Et
OH
Diethylstilboesterol Dienestrol
HC
3
HO
CH
3
OH
HO
HC
3
CH
3
CH
3
HC
3
CH
3
OH
HO
300
Pharmaceutical Chemistry of Natural Products
3. Oestrogens of plant origin
HO
O
O
O
OH
Coumestrol
Genistein
HO
OH O
O
OH
Oestrogens of Pharmaceutical Importance
Oestrogens of natural origin
Oestrone
Oestrone or (9 ,14 )-3-hydroxy-7,8,9,11,12,13,15,16-
octahydro-6 -cyclopenta[a]phenanthren-17(14 )-one
SS
HH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
HO
H
H
H
O
Oestrone was isolated by Butenandt and Doisy in 1929 from the urine of pregnant women. It is
the fi rst known member of sex hormones. The main source of oestrone is the urine of pregnant or
nonpregnant women, human placenta and adrenal cortex. It is a stable white substance existing
in three crystal forms.
The main function of oestrone is to induce the state of heat in the female animals and thus
acts in the control of uterine cycle. It also helps in the development of female secondary sex
characteristics by which they become different from males.
Synthesis of oestrone:
MeO
O
MeO
OH
O
O
CH =CHMgBr
2
OH
⫺
MeO
O
O
TsOH
Steroids and Hormones
301
O
H
MeO
H –Ni
2
O
MeO
(i) K/NH
(ii) CrO
3
3
HH
H
O
MeO
HO
HH
H
O
( ) Oestrone⫾
CHNHCl
55
⭈
Oestriol
Oestriol or (9 ,14 ,16 )-13-methyl-7,8,9,11,12,13,14,15,16,17-
decahydro-6 -cyclopenta[a]phenanthrene-3,16,17-triol
SSR
H
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
HO
H
H
H
OH
OH
18
It was isolated by Marrian in 1950 from the urine of pregnant women. It is useful in some cases
of oestrogen defi ciency, especially for the relief of menopausal symptoms and, in paediatrics, to
combat gonorrhoeal vaginitis. It occurs mainly in human placenta and pregnant women. It is
effective orally.
Synthesis of oestriol:
Route 1
Oestrone
Isopropenyl acetate
O
H H
H
HO
OAc
H
H
H
AcO
C H COOOH
Perbenzoic acid
65