Hormones

Hormones are agents secreted by endocrine glands

and transported by the blood to exert their
characteristic effects upon certain specific tissues
other than tssues or glands of origin.
There are 4 major chemical classes of hormones
• steroid hormones - i.e. progesterone
• peptide hormones - i.e. insulin
• amino acid derivatives - epinephrine
• prostaglandins and related compounds
 Steroid hormones
• Natural steroidal hormones are subdivided
according to physiological function into:
a. Female sex hormones: Estrogens and
Progesterone

b. Male sex hormones: Testosterone

C. Corticosteroids: Mineralocorticoids and

glucocorticoids
• Hormones are classified according to their building
block into:
Mechanism of Hormone Action

All hormone action is receptor mediated:

1. Steroid and thyroid hormones act via intracellular

receptors.

2. Peptide hormones and catecholamines bind to cell

surface receptors
 STEROID STRUCTURAL CHARACTERISTICS:

Phenanthrene
Cyclopentane

13
1 10 C D
2 14
A B
5 The parent precursor of steroids
- cholesterol
 Biosynthesis
O

Cholesterol side chain cleavge

Steroid dehydrogenase and
isomerase enz O
HO HO Pregnenolone
e
h yd r oxylas
O 17 a -
OH
O
Progesterone
HO
17a- hydroxy pregnenolone
17-20 lyase [desmolase]
O O
O Steroid dehydrogenase and
isomerase enz aromatase

O HO
HO
Dehydoepianderosterone Androstene dione Estrone

17-keto reductase Estradiol dehydrogenase

OH
OH
OH

5a-reductase aromatase
O
O
H HO
5 a-Dihydrotestosterone Testosterone Estradiol
Structure of Steroid Hormones
Substituents appear either above or below the plane or in
plane [if double bond present]
Steroids
Progestins
Glucocorticoids
Mineralocorticoids
Androgens
Estrogens
Vitamin D

Steroids are lipophilic molecules.

All steroids, except calcitriol, have
cyclopentanoperhydrophenanthrene structure (sterane).
• The basis of a steroid molecule is a four-ring structure:
three six-membered cyclohexan (A, B & C) and one five-
membered ring (D) in a fused ring system.
• These hydrocarbons are
cyclopentanoperhydrophenanthrenes.
angular R3
Methyl R1

R2 C D

A B

• Methyl groups are attached to C-10 & C-13

3α-hydroxy 17β-hydroxy-17α-methyl

HO CH
CH3 3
CH3

HO HO

3β-hydroxy
 Stereochemistry:
1-Rings A and B: may be fused trans or cis, affording steroids of the 5α- and
the 5β- series respectively.

2- Rings B and C: The fusion of these rings is trans.

3-Rings C and D: The fusion of these rings is trans in all steroids
except cardiac glycosides and food poisons.
 Steroid Nomenclature

• Steroidal carbocycles

H
H
H H

CHOLANE

2 angular Me + 8C side chain from C17

 CH3
H
H
H H
H H

ANDROSTANE ESTRANE
2 angular Me + no side chain from Only one angular Me + no side chain
C17 from C17
C-19 C-18

H
H
H H

PREGNANE 2 angular Me + 2C side chain from C17

(C21)
The stereochemistry of the hydrogen at C-5 (if present )
must be included in the name of the steroid (e.g. 5α-
estrane)
Instructions for Numbering
1. Numbering begins in ring A at C1 and proceeds
around rings A and B to C10, then into ring C
beginning with C11, and snakes around rings C and
D to C17.
2. The angular methyl groups are numbered 18
(attached to C13) and 19 (attached to C10).
The C17 side chain begins with C20, and the numbering
finishes in sequential order.
 General rules for naming
• First of all we determine type of ring whether it is estrane, androstane or
pregnane.
• Ring fusion : A/B → trans B/C → trans C/D → trans ( THEY’RE ALL
TRANS FUSED): in trans fusion : 5 , 9, 14 subs. are α.
• Naming of substituents:
• Location & orientation of substituents should be determined. They are
either suffix or prefix.
• One substituent → preferred to be suffix.
• Alkyl, halo & nitro → must be prefix.
• If more than one type of substituents: we follow the following preference
rule: ammonium salt
→acid→lactone→ester→aldehyde→ketone→alcohol→amine → ether.
• e.g., ammonium salt & acid → acid is prefix & ammonium salt is suffix.
• Prefixes are arranged alphabetically.
 Name

Substituents (prefixes with position & orientation).

◼ name of nucleus (estrane, pregnane…& if there is any

abnormality mentioned before nucleus) , then Unsaturation
(double or triple bond)

Suffix (parent)
Chemically:
a. Estrogens belong to estrane carbocycle
b. Progesterone and corticosteroids belong to the
pregnane nucleus
c. Testosterone belong to the androstane nucleus
• Substituents ………….. α & β
• The methyl groups of C-13 and C-10 ……
( numbered 18 & 19 respectively)

• In estrogens with an aromatic A ring, the methyl

group at C-10 is absent. CH3

H
H H

ESTRANE
 Estrogens

• Estrogens are the primary female sex hormones and are

responsible for development and regulation of female
reproductive system and secondary sex characteristics.
• Estrogens may also refer to any substance, natural or synthetic,
that mimics the effects of the natural hormone.
• They bind to and activate estrogen receptors (ERs).
• The steroid 17β-estradiol is the most potent and prevalent
endogenous estrogen.
• The three major naturally occurring forms of estrogen in women
are: Estrone (E1), Estradiol (E2) and Estriol (E3).
• Estetrol (E4) is produced only during pregnancy.
 Female sex hormone

GnRH
or LHRH FSH LH Regulate the ovary and
Hypothalamus [Link] production of sex hormones
LH &FSH promote follicle growth

GnRH = gonadotropin-releasing hormone

LHRH = luteinzing hormone -releasing hormone
Natural Estrogens

Most potent Less potent Least potent

 Estrogens : Biosynthesis
O

Cholesterol side chain cleavge

Steroid dehydrogenase and
isomerase enz O
HO HO Pregnenolone
e
h yd r oxylas
O 17 a-
OH
O
Progesterone
HO
17a- hydroxy pregnenolone
17-20 lyase [desmolase]
O O
O Steroid dehydrogenase and
isomerase enz aromatase

O HO
HO
Dehydoepianderosterone Androstene dione Estrone

17-keto reductase Estradiol dehydrogenase

OH
OH
OH

5a-reductase aromatase
O
O
H HO
5 a-Dihydrotestosterone Testosterone Estradiol
• SEX HORMONES
Female sex hormone
Physiological effects
 Metabolism

Estron-3sulfate

Estrone and estradiol are biochemically interconvertible by the

enzyme estradiol dehydogenase and yield the same metabolic
products. As both estrone and estradiol are converted by 16-
hydroxylase to estriol.

Inactivation of steroids involves reductions and conjugation to

glucuronides or sulfate to increase their water solubility.
 CH3OH
H
H
H H
HO
CH3OH
H
H OH
H H
HO
‫ال ص ور ب ح ث ن ت ي ج ة‬

3β-hydroxy-estra-1,3,5(10)triene-17-one

The most important estrogen feature is aromatic ring A

Estriol
CH3OH
H
H OH
H H
HO

Estra-1,3,5(10)-triene-3,16α,17β-triol
 Estrogens

• Estrogens are aromatic ring A steroids. The natural

hormones are estradiol, estrone and estriol. estetrol is
produced only during pregnancy.

• 3-Hydroxyestra-1,3,5(10),7-tetraen-17-one.
(An analogue of estrone of murine origin)
 Estradiol

CH3OH
H
H
H H
HO

• Estra-1,3,5(10)-triene-3,17β-diol
• 1,3,5(10)- Estratriene-3,17β-diol
Estradiol
✓The most potent endogenous estrogen when
administrated parentally.
✓Estradiol is not taken orally, WHY?
✓1) In the gut, bacterial flora act on ring D by
attacking from α face (due to steric hindrance at ß
face by angular Me) → degradation.
✓2) 1st pass effect in the liver either by: oxidation →
estrone (OR) hydroxylation → estriol.
✓ So estradiol has very week oral activity (large
amount is needed).
✓So estradiol is taken by injection as ester to prolong
its action.
15-20 times more potent than estradiol when 17-ethinyl protects from α Face
taken orally. Angular methyl protects from β Face

CH3OH CH
C
H
H H
CH3OH CH
HO C
17α-ethinylestradiol H
H H
17-ethinyl estra-1,3,5(10)-trien-3,17-diol
H3CO

Mestranol
Metabolized to ethinyl estradiol by O-demethylation
after oral administration
They are used in oral contraceptive
 Quinestrol

Orally active derivative of estradiol

Slowly release ethinyl estradiol → long acting

OH
C CH

17α-Ethynylestradiol-3-cyclopentyl ether
Synthesis
Mestranol

O CH3OH CH
C
H
H
H H
H H 1-(CH3)2SO4
H3CO
HO 2- KC CH / Liq. ammonia

or HC CMgBr/ H
Ethinyl Estradiol

CH3OH CH
C
H

17α-ethinylestradiol
H H
HO
Estradiol esters

• Estradiol is weakly active orally. It is used as its esters.

• Used to prolong its action …….. taken by injection.
• Used for long term therapy
• According to the available functional groups they are
either 3-, 3,17- or 17- esters.
• Estradiol benzoate:
-17-β-hydroxyestra-1,3,5(10)-trien-3-yl benzoate.
- Estra-1,3,5(10)-trien—3,17β-diol 17-benzoate.
• Estradiol dipropionate:
- Estra-1,3,5(10)-trien-3,17β-diol dipropionate
• Estradiol cypionate
- Estra-1,3,5(10)-trien-3,17β-diol 17 β-(3-cyclopentylpropionate)
• Estradiol valerate
- Estra-1,3,5(10)-trien-3,17β-diol 17 β-pentanoate (orally active)

They are prodrug, when administrated by I.M ……. slow hydrolysis of

the ester releases the free estradiol over prolonged period.
Estradiol-17 β-(3-cyclopentyl propionate)(Estradiol cypionate)
O
O

H
H H
HO

O
O
OCO(CH2)3CH3
H
H H
O

HO O

Estradiol -17 β -pentanoate (valerate)

 Orally active derivatives of estradiol
• Ethinyl estradiol
• Mestranol
• Quinestrol: (long duration)
3-Cyclopentyloxy-17α-ethynylestra-1,3,5(10)-
Trien-17β-ol (long duration) OH
C CH

• Estradiol valerate O

Estradiol -17 β-pentanoate

OCO(CH2)3CH3

- Esters used for long term therapy

- Prodrug
- When administered by I.M. HO

Slow hydrolysis of the ester release the free estradiol over

prolonged period
 Estramustine Na PO4
O
A nitrogen mustard linked to O P ONa

estradiol, usually as phosphate; used ONa

to treat prostatic neoplasms; also has O

radiation protective properties Cl

N O

Cl

Mechanism of action
• Estrogen → anti-androgenic.
• Nitrogen mustard “Alkylating moiety” → Alkylation of DNA in
cancer cells.
• Prostate tissues are rich in “ phosphatase enzyme” → drug
converted into active form in prostate tissues more than normal
cells (selectivity).
 Attenuated estrogens
[Conjugated estrogen]
O

Equilin : ∆7 estrone
( estrone + double bond at C7) HO
Equilin

- They comprise primarily a mixture of Na estrone

sulfate and Na equilin sulfate.

- They are used in menopause as replacement

therapy O

O
Na O S O
O
 Synthetic Nonsteroidal Estrogens

With same distance between 2 OH……….. estrogenic

activity.
They are no longer used as an estrogen in women, but
are used to treat prostate cancer in men.
Diethylstilbestrol

Trans –α,α-diethyl-4,4-stilbenediole (DES)

(E)-3,4-bis(4-hydroxyphenyl)-3-hexene
(E)-4,4'-(1,2-Diethyl-1,2-ethenediyl)bisphenol
•DES
•Diethylstilbestrol
synthesis
 Dienestrol OH

HO

• 3,4-BIS (P-hydroxyphenyl)-2,4-hexadiene
IUPAC NAME
• 4-[(2E,4E)-4-(4-hydroxyphenyl)hexa-2,4-dien-3-yl]phenol
Synthesis
Chlortrianisene

IUPAC
1-[1-chloro-2,2-bis(4-methoxyphenyl)ethenyl]-
4-methoxybenzene
Synthesis
• Antiestrogens
• Estrogen antagonists
• Estrogen blockers

They act by blocking the estrogen receptor(ER)

and/ or inhibiting estrogen production.
 Anti-estrogens
• Selective estrogen receptor degrader (SERD)
e.g. Fulvestrant.
• Selective estrogen receptor
modulators(SERMs)
e.g., Tamoxifen, Clomiphene, and Raloxifene.
• Aromatase inhibitors (AIs) like Anastrozole
• Anti-gonadotropins including androgens/
anabolic steroids, progestogens, and GnRH
analogues.
 Uses

• ER-positive breast cancer

• Infertility
• Male hypogonadism
• Gynecomastia (breast development in men)
Side effects:- hot flashes, osteoporosis
breast atrophy, and vaginal dryness and atrophy.
Selective estrogen receptor degrader (SERD)

Fulvestrant
OH

O F
F
S F
HO
F
F

(7α,17β)-7-[9-[(4,4,5,5,5-Pentafluoropentyl) sulfinyl
nonyl]estra-1,3,5(10)-triene-3,17β-diol

55
• Fulvestrant is a drug treatment of hormone
receptor –positive metastatic breast cancer in
post-menopausal women.
• It works by binding to the estrogen receptor and
making it more hydrophobic, which make the
receptor unstable causing the cell's normal
protein degradation processes to destroy it.
• It is an estrogen receptor antagonist which
works both by down-regulating and by
degrading the estrogen receptor.

56
 SERMs (Selective Estrogen Receptor Modulators)

• Clomiphene: antagonist at hypothalamus

Treatment of ovulatory dysfunction
• Tamoxifen: agonist at bone and uterus
antagonist at breast
Breast cancer
• Raloxifene: agonist at bone and uterus
antagonist at breast
Osteoporosis, breast cancer

57
 SERMs (Selective Estrogen Receptor Modulators)

• Selectivity is possible because

ER-α and/ or ER-β show differential tissue
expression
• Conformation dependent binding to DNA and
transcription factors
• Tissue dependent responses ranging between
pro-estrogenic, partially estrogenic and anti-
estrogenic effects

58
• SERMs are used for various estrogen-related
diseases including:
- Treatment of ovulatory dysfunction in the
management of infertility
- Reduction risk of breast cancer
- Treatment and prevention of postmenopausal
osteoporosis

59
 Antiestrogens (Estrogen Antagonists)

Anti-estrogen are used to modify reproductive processes &

treatment of estrogen dependent breast cancer.

Clomiphene
Used as mixture of Z & E isomers
(synergistic)

Cl
It is used orally as a mixture isomers to
induce ovulation for treatment of an
ovulatory infertility [negative feed back
O
mechanism]
N At ↑ doses of clomiphene → ↑↑ FSH
→ ↑ No. of mature ova → multi-birth .

60
 TAMOXIFEN

It is an antiestrogen used to treat early and advanced breast

carcinoma in postmenopausal women. Tamoxifen and
clomiphene like diethylstilbesterol can bind to the estrogen
receptor.

Assay of clomiphene & tamoxifen

[non-aqueous titration]

basic nitrogen can be titrated by HClO4 in glacial acetic acid.

61
SYNTHESIS

O MgBr

C2 H5 O N

C2H5

O
N

(E) and (Z) isomer

62
 Estrogen Synthesis Inhibitors

Aromatase inhibitors

- Aromatase inhibitors (AIs) are class of drugs

used in treatment of breast cancer in post-
menopausal women.
- It inhibits the enzyme aromatase, which is
responsible for converting androgens (produced
by women in the adrenal glands) to estrogens.

63
 Estrogen Synthesis Inhibitors
Aromatase Inhibitors
- Steroidal: exemestane (AROMASIN)
- Non-steroidal: anastrozole (ARIMIDEX), letrozole
(FEMARA)
✓ Specifically block the local production of estrogens
in hormonally-responsive tissues or block the action
of estrogen on receptors.
✓ Second-line treatment for breast cancer in patients
whom tamoxifen therapy is unsuccessful, but new
studies rapidly proving its efficacy and promoting
earlier use
✓ Aromatase inhibitors do not have the bone
protecting activity of tamoxifen, and adjuvant
therapies to prevent bone loss are in trials
 Anastrozole

2,2'-(5-((1H-1,2,4-triazol-1-yl)methyl)-1,3-phenylene)bis(2-
methylpropanenitrile)

65
 Steroidal aromatase inhibitor

• It is an enzyme activated irreversible inhibitor of

aromatase.
• Planarity of ring (A) is essential for the affinity of the
compound to aromatase
• Exemestane

66
- Exemestane is an oral steroidal aromatase inhibitor used
in the adjuvant treatment of hormonally-responsive (also
called hormone-receptor-positive, estrogen-responsive)
breast cancer in postmenopausal women.

- It acts as a false substrate for the aromatase enzyme, and

is processed to an intermediate that binds irreversibly to the
active site of the enzyme causing its inactivation.

67
 Exemestane

6-Methyleneandrosta-1,4-diene-3,17-dione

68
 SAR of Estrogens
✓Steroid nucleus is not necessary for estrogenic
activity.
✓Estradiol is not effective orally due to rapid
metabolism in liver but presence of ethinyl group at C-
17 position increase the resistance to metabolic
inactivation and make the compound orally active.
✓Methylation of 3-OH group e.g. mestranol make the
compound orally active.
✓Ester derivatives (acetate and benzoate) of the
naturally occurring and synthetic estrogens have
prolonged action.
✓Insertion of OH group at C-6, C-7 and C-11 position
reduces estrogenic activity. 69
 Progestins
(Progesterones)

Progesterone
CH3COCH3
H
CH3 H

H H
O

Pregn-4-en-3,20-dione

70
 CH3
Synthesis CH3 H

H H
HO

From stigmasterol
(Soya been oil) H3C
CHO
CH3

CH3 H
Oxidation 3 steps H H
Then two steps HO

…….Progesterone
CH3COCH3
H
CH3 H

H H
O

71
 Medicinal uses:

As contraceptive in combination with estrogens

➢ Habitual abortion: Progesterone maintain and protect the fetus,
therefore progestine may be given to women who are prone to abortion.
➢ Excessive uterine bleeding: Estrogen and progestin deficiency is probably
the cause; however the progestin norethynodrel can be used successfully
since it possesses some estrogenic activity.
➢ Dysmenorrhea: A more normal menstrual cycle is obtained. Estrogens
used for this condition may be supplemented with progestins during the
last several days of treatment.
➢ Amenorrhea: An artificial menstrual cycle could be induced by
administration of an estrogen for 20 days, supplemented with
progesterone from the 5th to the 25th day. Menstruation occurs on
withdrawal of treatment.
➢ Diagnosis of pregnancy: Progesterone in combination with an estrogen is
given. Withdrawal bleeding would occur in cases of amenorrhea not due to
pregnancy.
➢ Premenstrual tension.
72
- Progestins derived from progesterone

- Progestins derived from testosterone and

nortestosterone

73
 Synthetic progestins:
1] 17 α-Hydroxyprogesterone derivatives

The parent 17 α -hydroxy progesterone is inactive so, use 17α-

Ester derivatives.
Hydroxyprogesterone caproate

CH3COCH3-
OCO (CH2)4CH3
CH3 H
Long duration
H H Parentally not orally due to 1st pass
O effect

17α-hydroxy-pregn-4-en-3,20-dione hexanoate

74
Medroxy Progesterone Acetate
(Depo-provera®)

CH3COCH3
OCOCH3
CH3 H

H H
O
H3C H

17α-Hydroxy-6α-methylpregn-4-en-3,20-dione acetate
Taken by injection / 3months (long duration).
Makes hostile medium for fertilization (by ↑ viscosity of vaginal
fluids making it difficult for sperms to move to fertilize ovum).
called progesterone-only contraceptive

75
✓It is very active orally, and has such a long duration of action
intramuscularly that it cannot be used IM for treating many
menstrual disorders.
✓It adds a 6α-methyl group to the 17α-hydroxy progesterone
structure to greatly decrease the rate of reduction of the 4-
en-3-one system. The 17α-acetate group also decreases
reduction of the 20-one, just as with 17α-caproate.
✓Uses: Action, uses and side effects are those of progestins in
general. It is used as an oral contraceptive.
Assay: Spectrophotometrically at 241 nm.

76
 Progestins derived from testosterone and
nortestosterone
• Testosterone & Nortestosterone

CH3OH CH3OH
H H
CH3 H H
H H H H
O O

77
 Norethindrone …..Norethisdrone

Ethisdrone was synthesized to find an orally active androgen but

late it is proved to be an effective oral progestin and used in
treatment of menstrual dysfunctions.

17β-Hydroxy-19-nor pregn-4-en-20-yn-3-one
CH3OH CH CH3OH CH
C C
H H
Norethynodrel
H H H H
O O

5-10 times more progestational activity

17β-Hydroxy-19-nor pregn-5(10)-en-20-yn-3-one

78
 Dimethisterone

CH3OH C CH3
C
H

H H
O
CH3

Uses:
A progestin with action and uses similar to norethindrone. Its
estrogenic and androgenic activity are both weak. It is given
with ethinylestradiol for oral contraception.

17β-Hydroxy-6α-methyl-17α-propynyl-androst-4-en-3-one

79
 Norgestrel

It has an ethyl group instead of the C13-methyl group but has

similar biological activities.
Uses: It is used only in oral contraceptives
OH
C CH
H

H H
O

13-Ethyl-17β-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one
80
 RU 486 (Mifepristone)

Abortifacients
Antiprogesterone used as abortifacient in the first two months of
pregnancy, and in smaller doses as an emergency contraceptive
CH3
N
H3C OH
CH3
C C

11β-(p-Dimethylamino phenyl)-17β-hydroxy-17α-(prop-1-
ynyl)estra-4,9-dien-3-one

81
◼ Oxendolone

16 β-Ethylestr-4-en-17 β-ol-3-one
16 β-Ethyl-19-nortestosterone
Oxendolone is an antiandrogen

82
Cortisone
17α,21-Dihydroxy-pregn-4-en-3, 11, 20-trione

83
◼ Epristeride is a steroid acid

17-(Tert-butylcarbamoy[) androsta-3,5-diene-3-carboxylic acid

Epristeride is a 5α-reductase inhibitor

84
 References

✓Foye’s “Principles of Medicinal Chemistry, Seventh Edition,” By David A.

Williams and Thomas L. Lemke, Lippincott Williams & Wilkins Publishers,
New York, 2012.
✓Burger's Medicinal Chemistry and Drug Discovery 6th Ed (Vol. 1-6); Donald
J. Abraham; ISBN 0-471-27401-1; John Wiley & Sons, Inc; 2003.
✓Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical
Chemistry. 12th Edition, J.N. Delgado and W.A. Remers, Lippincott-Raven
2011.
✓Graham L. Patrick, An Introduction to Medicinal Chemistry, 4th Edition, ISBN
978-0-19-923447-9Oxford University Press Inc., New York, 2009.
✓Gareth Thomas Medicinal Chemistry, An Introduction, 2ndEdition. Wiley-
Inter-science (2008).
✓Drug bank

85