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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4

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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