Medicinal Chemistry II

PMC307
Lecture 06 (Hormones, Part 2)

Dr. Sally Tarek Mahmoud, PhD

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Steroidal Hormones
Cyclopentanoperhydrophenanthrene
C D
A B
Steroidal Template
Classification

Corticosteroids Sex Hormones

Glucocorticoids Estrogens

Mineralocorticoids Androgens

Progestins
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Steroidal Hormones
Numbering

12
17
11 13
C D 16
1 9 14
15
2 10 8
A B
3 5 7
4 6
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Steroidal Nuclei
With one angular methyl
(C18)

18
12
17
11 13 No side chain at C17
Estrane C D 16
1 9 14
15
(18 Cs) 2
A
10
B
8

3 5 7
4 6
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Steroidal Nuclei
With two angular methyl groups
(C18/C19)
18
12
17
11 13 No side chain at C17
19
C 14 D 16
Androstane
1 9
15
2 10 8

(19 Cs) 3
A 5
B 7
4 6
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Steroidal Nuclei

With two angular methyl groups

(C18/C19)
20 21 Two carbons at the
18
12
side chain at C17
17
11 13
Pregnane 19
C D 16
1 9 14
(21 Cs) 2
A
10
B
8
15

3 5 7
4 6
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Steroidal Nuclei

With two angular methyl groups

(C18/C19) 21 Eight carbons at the
22
18
20
23
24
26 side chain at C17
25
12
17

Cholestane
11 13

1
19
9
C 14
D 16
27

(27 Cs)
15
2 10 8

3
A 5
B 7
4 6

Parent Compound
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Stereochemistry 10
Three Ring Fusions
Angular Methyl are in 𝛃𝛃-Configuration
C
D
C
D
A
B
A
5 B
All TRANCE A/B: Trans A/B: Cis
B/C: Trans
natural C/D: Trans 5𝛃𝛃-Configuration B/C: Trans
C/D: Trans
Stable of lower energy
Most steroids are in all trans configuration Less stable of higher energy
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Steroidal Nomenclature

OH O
OH
HO OH

HO O O
Estradiol Testosterone Cortisone

Estra-1,3,5(10)-triene-3,17β-diol Androst-4-en-17β-ol-3-one 17α,21-Dihydroxypregn-4-ene-

3,11,20-trione
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Corticosteroids
Corticosteroids are a class of steroidal hormones
that are produced in the adrenal cortex

Corticosteroids

Glucocorticoids Mineralocorticoids
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Corticosteroids Glucocorticoids • Regulation of glucose metabolism
• Produced in the adrenal cortex
glucose + cortex + Steroid
• Steroidal structure

Regulation of
Glucocorticoid’s Secretion
• CRH: Corticotropin-releasing hormone
• ACTH: Adreno-corticotropic hormone

High levels of glucocorticoids serve as feedback Cortisol

inhibitors of ACTH production and suppressing further Cortisone
synthesis of glucocorticoids
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Corticosteroids Glucocorticoids
Pharmacological Actions
Glucocorticoids bind to glucocorticoid receptors (nuclear receptors) showing the following effects:
1. Carbohydrate metabolism: gluconeogenesis.
2. Stimulate protein catabolism (except in the liver) and lipolysis, providing energy that are needed for
glucose synthesis. Glucocorticoid insufficiency may result in hypoglycemia (for example, during stressful
periods or fasting).
3. Increase resistance to stress: By raising plasma glucose levels, glucocorticoids provide the body with
energy to combat stress caused by trauma, fright, infection, bleeding, or debilitating disease.
4. Anti-inflammatory action:
a) Decreasing production and release of proinflammatory cytokines.
b) Inhibit phospholipase A2 , decreasing the production of prostaglandins and leukotrienes.
5. Immuno-suppressive action.
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Corticosteroids Glucocorticoids
Therapeutic Uses:
1- Antiasthma by inhalation.
2- Immunosuppressant Addison disease is caused by adrenal cortex
dysfunction (as diagnosed by the lack of
3-Antiallergic (topically or in case of anaphylaxis)
response to ACTH administration).
4-Rheumatoid arthritis
5-As adjuvant therapy for cancer & hepatitis Cushing syndrome is caused by hypersecretion
of glucocorticoids (hypercortisolism) that
6-Used topically (psoriasis & pruritis).
results from excessive release of ACTH by the
7-Replacement therapy for primary adrenocortical insufficiency
anterior pituitary or an adrenal tumor
(Addison disease)

Side effects of glucocorticoids:

Causes Na+ & H2O retention due to their mineralocorticoid activity (retain
Na & excrete K) → moon face & edema.
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Corticosteroids Glucocorticoids
Cortisol O
HO OH
Natural Glucocorticoids HO

• Cortisol is synthesized from cholesterol

• Metabolized by 11β-hydroxysteroid dehydrogenase (11β-HSD)
O
enzyme to the more active CORTISOL (Hydrocortisone) Pregnane steroidal nucleus
with:
• 3-oxo “carbonyl”
• 4-5 double bond
• 11- β-hydroxy
• 17α-hydroxy
• 20-oxo “carbonyl”
• 21-hydroxy
 Glucocorticoids
17

Classification acc. To duration of action of:

A-Systemic:

• Short acting:
1-Cortisone. 2- Hydrocortisone
• Intermediate acting:
1- Prednisolone 2-Methyl prednisolone 3- Triamcinolone
• Long acting:
1. Dexamethasone 2. Betamethasone
B- Local:
1-Beclomethasone
2-mometasone
3- Fluticasone.
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Corticosteroids Glucocorticoids
Synthetic Glucocorticoids
To improve the pharmacokinetics and decrease side effects attempts are done by structure
modifications as:
1) Introduction of a double bond between C1& C2:(∆1)

• Increase GC activity
• enhance anti-
inflammatory activity
• Decrease salt retaining
activity
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∆1 of cortisone and hydrocortisone, & 6 α methyl of the latter
Prednisone Prednisolone O
Methylprednisolone
Prednisone is ∆1 cortisone O
HO OH OH
HO
O HO HO
HO OH
O

O O

O
• A derivative of prednisolone with 6α-
• it’s a prodrug, activated by methyl which act as metabolic blocker.
11𝛃𝛃-HSD to the active
• Formulated as succinate ester (rapidly
PREDNISOLONE
acting) or acetate salt (depot)

Indications: anti-inflammatory, immuno-suppressive

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Corticosteroids Glucocorticoids
Synthetic Glucocorticoids
2) 9α- F derivatives when combined with ∆1 & C16 substitution :
Dexamethasone
• Dexamethasone is ∆1 cortisol derivative with 9α-F and 16α-methyl
O
• 9-fluro-substitution increase the acidity of 11-OH and so increases the HO OH
HO
binding to glucocorticoid receptor in addition to improving the
pharmacokinetics.
• 16-methyl substitution decreases the mineralocorticoid effects. F
O
• Used orally (tablet, syrup) or ampoules (sodium phosphate) or eye drops
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Corticosteroids Glucocorticoids
Synthetic Glucocorticoids
Betamethasone
2) 9α- F derivatives when combined with ∆1 & C16 substitution :
O
HO OH
• Betamethasone is ∆1 cortisol derivative with 9α-F and 16β-methyl HO
• Used orally (tablet), systemically (ampoules), topically (cream)
F
O
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Corticosteroids Glucocorticoids
Synthetic Glucocorticoids
O
HO OH
HO
OH

F
O
Triamcinolone
acetonide salt
• 16α- OH eliminate mineralocorticoid activity
• Used as C16α,17α acetonide salt; It is a more potent
than triamcinolone and to about 8 times as potent as
prednisone
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Topically acting glucocorticoid:

O
O
O O Cl
HO

Cl
O Mometasone Furoate
• Used as furoate ester & acts as a prodrug.
• It is dexamethasone with 9 Cl instead of 9F
and 21 Cl instead of 21 OH.
Fluticasone
• Used as either furoate and
propionate esters as inhaler or
nasel spray.
• It is dexamethasone with extra
6-F and -SCH2F instead of
CH2OH
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Corticosteroids Mineralocorticoids

Aldosterone Salt & Water Retention

OH
O
O • Mineralocorticoids help to control fluid status and concentration
HO of electrolytes, especially sodium and potassium.

• Aldosterone acts on distal tubules and collecting ducts in the

O kidney, causing reabsorption of sodium, bicarbonate, and

water.
Pregnane with 18-aldehyde

• Aldosterone is part of the renin–angiotensin–aldosterone

system (RAAS) controlling homeostasis and blood pressure.
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Corticosteroids Mineralocorticoids

Fludrocortisone
O
HO OH
O
• It is mineralocorticoid receptor agonist
• Used for adrenal insufficiency (as in Addison’s disease)
F
O • It increases the blood pressure, can be used for
orthostatic intolerance.
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Corticosteroids Mineralocorticoids

Spironolactone
O

• It is a spiro compound with 7-thioester substitution

O S
• It acts as mineralocorticoid receptor antagonist

O
• It is a potassium-sparing diuretic, used for
hypertension.