STRUCTURE ACTIVITY RELATIONSHIP OF STEROIDS
Speaker: Dr Rachana Menon
As we go along…
• Introduction to SAR
• Corticosteroids
• Sex hormones
• Cardiac glycosides
Chemical structure
A chemical structure includes molecular geometry, electronic structure, and crystal structure of a molecule.
Biological structure
Biological activity is an expression describing the beneficial or adverse effects of a drug on living matter
The structure–activity relationship (SAR) is the
relationship between the chemical or 3D structure of a
molecule and its biological activity.
The analysis of SAR enables the determination of the
chemical groups responsible for evoking a target
biological effect in the organism
To determine as accurately as possible the limits of
variation in the structure of a chemical that are
consistent with the production of a specific effect
To define the ways, which alterations in structure and
thereby the overall properties of a compound influence
endpoint potency
NEED FOR SAR STUDIES
Structure–activity relationships are usually determined by
making minor changes to the structure of a lead to produce
analogues
Those changes are..
• Size and shape of the carbon skeleton
• Nature and degree of substitution and
• Stereochemistry of the lead
WHEN SAR STUDIES ARE DONE?
• Chemical compound screening
• Lead molecule•
Pharmacophore
pruning
• Lead molecule:
Chemical compound that has pharmacological activity, chemical structure is used as a starting point for chemical modifications in order to improve potency selectivity or phamacokinetic parameters.
• Pruning: the refinement of lead structure. It is done to determine
the pharmacophore
• Pharmacophore: an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule
SAR OF STEROIDS
Why SAR of Corticosteroids?
Chemical modifications leads to generation of
derivatives with
• Greater separation of glucocorticoid &
mineralocorticoid activity
• Different potency & duration of action
Cyclopentano perhydro phenanthrene nucleus
•All contain 21 carbon atoms.
•Steroid nucleus
•α,β substitution
All require 3 keto group and 4,5 unsaturation, carbonyl group in C20
Glucocorticoid activity requires 11 β hydroxyl(OH) group , an α-hydroxyl group linked to C17
Additional unsaturation of Ring A
Enhance antiinflammatory
effect
increase in GC activity
Slow metabolism
Salt retaining activitydecreases
glucocorticoid/mineralocorticoid
potency ratio
•Increases glucocorticoid activity, •Enhanced glucocorticoid/ mineralocorticoid potency ratio. •Metabolized more slowly than hydrocortisone
• Changing single bond between C1 & C2 into the double,
the anti-inflammatory effect enhances and salt & water
effects weakens;
• Cortisone→ prednisone
• Hydrocortisone → prednisolone
• Adding a -CH3 to C6, the anti-inflammatory effect
enhances more;
• Prednisolone→ 6-methyl-prednisolone
Some structural changes
6 α substitution on Ring B
Increase GC activity
6α-Fluorination
• 6α-fluoro has less salt retention properties than 9α-fluoro.
• Fluocinolone
Fluorination at 9 alpha
• Resistant to local
destruction
Enhances both glucocorticoid and mineralocorticoid activity
Fludrocortisone (9-fluorocortisol) • enhanced activity at the GR (10 times relative to
cortisol) • greater activity at the MR (125 times relative to
cortisol).
9 α fluorination of Ring B
Enhances GC & MC activity
• Hydrocortisone→fludrocortisone→dexametha
sone & triamcinolone
the 9-fluoro derivatives
Anti-inflammatory effect
enhances and salt-
retaining effects weakens
further.
C 16
Acetonide b/w OH groups at C16 & C17
1,2 double bond in ring A + other substitutions
at C16 on ring D
Substitution at C16 on ring D
More GC activity & anti inflammatory activityEliminates MC activity
9α-chlorination
• 9α-chloro derivative of betamethasone• Beclomethasone dipropionate
– Increase stabilization – Increase lipophilicity– Increase bronchial tissue absorption– Increase duration of action
9α-chlorination
17 α hydroxyl group on ring D- esterification of the hydroxyl group
IMPORTANT FOR GC ACTIVITY-
optimal potency
Valerate at C17Propionate at C17 and C21Substitution group at C21 with chlorine
Lipophilicity & topical/systemic potency ratio
• Acetonide b/w OH groups at C16 & C17
• Esterification of OH groups with Valerate at C17
• Esterification of OH groups with propionate at
C17 & C21
• Substitution of OH group at C21 with Chlorine
Mineralocorticoid activity requires
Aldehyde group at C18 on ring
In a nutshell..
Changes that alters mineralocorticoid activity
• Aldehyde group in the C18
• Fluorination at the 9α position
on ring B
• 6α substitution on ring B
• Substitution at C16 on ring D
Changes that increase glucocorticoid activity
• Additional double bond b/w 1 & 2
carbon atoms
• Alpha methylation at 6th position
• Alpha fluorination at 9th position
• Substitution at 16th position In a
nutshell
Estrogen, Progesterone, Androgen
Testosterone, it lacks the 2-carbon side-chain attached to the 17 position, making it a 19-carbonsteroid .
21-carbon3-keto D4
18-carbon
ESTROGEN
•17-estradiol
•Estrone
•Estriol
High-affinity binding to both receptors
Ethinyl substitutions at the C17 position greatly increase oral
potency by inhibiting first-pass hepatic metabolism.
• Steroidal structures is not essential for activity.
• Alkylation of the aromatic ring decrease the activity.
Polyhydroxylated nonsteroidal compound with a benzothiophene core.
7-alkylamide derivate of estradiol
l
Points to rememberAromatic ring with C-3-OH is essential for activity.
Steroidal structures is not essential for activity.
Alkylation of the aromatic ring decrease the activity.
The 17b-hydroxyl with constant distance from 3-OH is
essential for activity.
Unsaturation of ring B decreases the activity.
17alpha- and 16 position when modified enhance the
activity.
PROGESTINS
• Compounds with biological activities similar to those of progesterone
4-3-one A-ring structure in an inverted 1 beta 2 alpha-conformation
Contd..
Steroidal nucleus essential for activity.
Have some androgenic activity.
Removal of the 19 CH3 increase activity.
Unsaturation of ring B or C increase the activity.
Removal of the keto function remove androgenic activity
17-Hydroxyprogesterone /Hydroxyprogesterone caproate
• Progestational activity .Used parenterally due to first-
pass hepatic metabolism.
• Substitutions at the 6-position of the B ring yield orally
active Medroxyprogesterone acetate
• Selective progestational activity.
An ethinyl substituent at C17
decreases hepatic metabolism and
yields orally active
Lack the C19 methyl group
• Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent
•Replacement of the 13-methyl group of norethindrone with a
13- ethyl substituent
•More potent progestin than the parent compound but has Less
androgenic activity
•Norgestimate, Desogestrel,Gestodene, Nomegestrol,
Nestorone, Trimegestone
ANDROGENS
• Anabolic steroids, technically known as anabolic-
androgenic steroids (AAS), are drugs that are
structurally related to the cyclic steroid ring system and
have similar effects to testosterone in the body.
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53
4
2
Therapeutic Androgen preparations
Esterifying a fatty acid to the 17 hydroxyl group compound that is even more lipophilic
LYMPHATIC SYSTEM
Retarded its hepatic catabolism
They are less androgenic than
testosterone itself, they cause
hepatotoxicity
Cardiac glycosides
Cardenolide : one double bond, lactone ring
5 member lactone ring (unsaturated) attached at C17beta position
of steroidal nucleus.
Bufadienolide: contain two double bonds, lactone ring
Has six member ( unsaturated ) lactone ring attached at C-17 alpha – position
Example:
Squill bulb glycoside
Scillaren
Examples:• Digitalis purpurea- Digitoxin, Digoxin • Digitalis lanata- Digoxin, lanatosides,
Deslanoside • Strophanthus gratus- Ouabain
• The steroidal aglycone of the glycosides is
responsible for cardiac activity.
• Sugars provide favorable solubility and
distribution, affect its potency and duration of
action.
Sugar moeity
The hydroxyl group at C-3 of the aglycone portion is
usually conjugated to a monosaccharide or a
polysaccharide with β-1, 4-glucosidic linkages.
The presence of an O-acetyl group on a sugar greatly
affects the lipophilic character and pharmacokinetics of
the entire glycoside.
These sugars predominantly exist in the cardiac
glycosides in the β-conformation.
Rings A-B and C-D are cis fused, while rings B-C have a
trans fusion
characteristic "U" shape
Two angular methyl groups at C-10 and C-13
Hydroxyl groups are located at C-3, the site of the sugar attachment, and
at C-14.
Rapid onset of action
Unsaturated lactone Ring
Points to remember
Steroidal nucleus must be present.
• 3b-OH group involved in glycosidic linkage.
• 14b-OH group at C-14.
• A/B ring junction cis
• B/C ring junction trans
• C/D ring junction cis
• The presence of lactone ring