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7/25/2019 Structureactivityrelationship Copy 140507102106 Phpapp02

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STRUCTURE ACTIVITYRELATIONSHIP OF STEROIDS

Speaker: Dr Rachana Menon


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As we go along

Introduction to SAR

Corticosteroids

Sex hormones

Cardiac glycosides


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Chemica !"r#c"#re

A chemical structure includes molecular geometry,electronicstructure, and crystal structure of a

molecule.

$ioo%ica !"r#c"#re

Biological activity is an expression describing thebeneficial or adverse effects of a drug on living matter


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he structureactivity relationship!SAR" is the

relationship bet#een the chemical or $% structure of

a molecule and its biological activity.

he analysis of SAR enables the determination of

the chemical groups responsible for evo&ing a target

biological effect in the organism


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o determine as accurately as possible the limits of

variation in the structure of a chemical that are

consistent #ith the production of a specific effect

o define the #ays, #hich alterations in structure and

thereby the overall properties of a compound influenceendpoint potency

NEED FOR SAR STUDES


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Structure'activity relationships are usually determined by

ma&ing minor changes to the structure of a lead to produce

analogues

Those changes are..

Si!e and shape o" the car#on s$eleton

Nature and degree o" su#stitution and

Stereochemistry o" the lead


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WHEN SAR STUDIES ARE DONE?

Chemical compound

screening

Lead molecule

Pharmacophore

pruning


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%ead 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 phamaco&inetic parameters.

&runing' the refinement of lead structure. It is done to determine

the pharmacophore

&harmacophore( an abstract description of molecularfeatures #hich are necessary for molecular recognition

of a ligand by a biological macromolecule
http://en.wikipedia.org/wiki/Molecular_recognitionhttp://en.wikipedia.org/wiki/Macromoleculehttp://en.wikipedia.org/wiki/Macromoleculehttp://en.wikipedia.org/wiki/Molecular_recognition


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SAR OF STEROIDS


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Why SAR ofCorticosteroids?

Chemical modifications leads to generation of

derivatives #ith

)reater separation of glucocorticoid *

mineralocorticoid activity

%ifferent potency * duration of action


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Cyclopentano perhydrophenanthrene nucleus


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All contain () car#on atoms*

Steroid nucleus+, su#stitution


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A reire ' ke"o %ro#p an(

)*+ #n!a"#ra"ion*carbonylgroup inC20


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-lucocorticoid activity re.uires )) hydro/yl0O12 group , an +3hydro/ylgroup lin$ed to

4)5


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Additional unsaturationof Ring A

Enhanceantiinaato

ry e!ect

increasein "C

acti#ity

Slowetaboli

s

Sa" re"ainin%ac"i,i"-

(ecrea!e!

glucocorticoid$

ineralocorticoid potency

ratio


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Increases glucocorticoid activity,Enhanced glucocorticoid !ineralocorticoid

"otency ratio#

$eta%oli&ed !ore slo'ly than hydrocortisone


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Changing single bondbet#een C+ * C into the double,

the anti-inflammatory effect enhancesand salt * #ater

effects #ea&ens

Cortisone/ prednisone

0ydrocortisone / prednisolone

Adding a -C0$to C1, the anti-inflammatory effectenhances more

2rednisolone/ 1-methyl-prednisolone

Some structural changes


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% & substitution on Ring'

Increa!e .Cac"i,i"-


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%&()luorination

%&(fluoro has less salt retentionproperties than *&(fluoro+

)luocinolone


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F#orina"ion a" / apha

Resistant to

local

destruction

Enhances both glucocorticoid

and mineralocorticoid activity


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Fludrocortisone (9-fluorocortisol)

enhanced activity at the (R )*+ ti!es relative tocortisol

greater activity at the $R )*-. ti!es relative to

cortisol#


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/ 0 1#orina"ion o2 Rin% $

Enhances "C ,

-C acti#ity


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.ydrocortisone/udrocortisone/deaetha

sone , triacinolone

the *(uoroderi#ati#es

Anti3in"lammatory e""ect

enhances and salt3

retaining e""ects 6ea$ens

"urther*

C 16

Acetonide b$w 1. groups atC% , C3

3*4 (o#5e 5on( in rin%A 6 o"her !#5!"i"#"ion!

a" C37 on rin% D


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Substitution at C% on ring 4

More .C ac"i,i"- 8 an"i in1amma"or-ac"i,i"-

Eimina"e! MC ac"i,i"-


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*&(chlorination

*&(chloro deri#ati#e ofbetaethasone

'ecloethasone dipropionate' 5ncrease stabili6ation

' 5ncrease lipophilicity

' 5ncrease bronchial tissue

absorption' 5ncrease duration of action


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*&(chlorination


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39 0 h-(ro- %ro#p on rin% D;e!"eri


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Mineraocor"icoi( ac"i,i"- reire!

Aldehydegroup atC= on ring


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In a n#"!he>>

Changes that altersineralocorticoidacti#ity

Aldehyde group in the C+7

8luorination at the 9: position

on ring B

1: substitution on ring B

Substitution at C+1 on ring %


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Changes that increase glucocorticoid activity

Additional dou#le #ond #86 ) 9 (

car#on atoms

Alpha methylation at :thposition

Alpha "luorination at ;thposition

Su#stitution at ):thposition

5n anutshell


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Estrogen, &rogesterone, Androgen

Te!"o!"erone*i" ack! "he 4;car5on !i(e;chaina""ache( "o "he 39 po!i"ion* makin% i"

a 19-carbon

21-carbon3-keto D4

18-carbon


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ES8R1"E939;e!"ra(io

E!"rone

Estriol

E"hin- !#5!"i"#"ion! a" "he C39


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Hi%h;a?ni"- 5in(in% "o

5o"h recep"or!

-po!i"ion %rea"- increa!e ora

po"enc- 5- inhi5i"in%


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53al$ylamide derivate o"


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&olyhydro/ylated nonsteroidal

compound 6ith a #en!othiophene core>

53al$ylamide derivate o"

estradiol


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7oints to reeber

Aromatic ring #ith C-$-40 is essential for activity.

Steroidal structures is not essential for activity.

Al&ylation of the aromatic ring decrease the activity.

he +5b-hydroxyl #ith constant distance from $-40 is

essential for activity.

;nsaturation of ring B decreases the activity.

+5alpha- and +1 position #hen modified enhance the

activity.


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PRO.ESTINS

Compounds #ith biological activities similar to those of

progesterone


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Con"(>>

Steroidal nucleus essential for activity.

0ave some androgenic activity.

Removal of the +9 C0$increase activity.

;nsaturation of ring B or C increase the activity.

Removal of the &eto function remove androgenic activity


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3(.ydroyprogesterone $1ydro/yprogesterone

caproate

2rogestational activity .;sed parenterally due to first-

pass hepatic metabolism.

Substitutions at the 1-position of the B ring yield orally

active


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An ethinyl substituent at C+5

decreases hepatic metabolism and

yields orally active

%ac$ the 4); methylgroup


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Repacemen" o2 "he 3';me"h- %ro#po2 nore"hin(rone =i"h a 3';e"h-!#5!"i"#en"

Replacement o" the )=3methyl group o" norethindrone 6ith a

)=3 ethyl su#stituent

=ore potent progestin than the parent compound but has >ess

androgenic activity

Norgestimate, Desogestrel,-estodene,Nomegestrol,

Nestorone, Trimegestone


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ANDRO.ENS

Ana#olic steroids, technically &no#n as ana#olic3

androgenic steroids!AAS", are drugs that are

structurally related to the cyclic steroidring system and

have similar effects to testosteronein the body.

)
http://en.wikipedia.org/wiki/Steroidhttp://en.wikipedia.org/wiki/Testosteronehttp://en.wikipedia.org/wiki/Testosteronehttp://en.wikipedia.org/wiki/Steroid


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)

>$

)

4


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Therape#"ic An(ro%en prepara"ion!

Esteri"ying a "atty acid to

the )5

hydro/yl group

compound that is even

more lipophilic

LYMPHATICSYSTEM

8hey are lessd i h


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Retarded its hepatic

catabolism

androgenic thantestosterone itself

they causehepatotoicity


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Car(iac %-co!i(e!

4ardenolide( one double bond, lactone ring ? member lactone ring !unsaturated" attached at C+5beta position

of steroidal nucleus#


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'ufadienolide@contain t'o dou%le %onds,lactone ring

Has si/ !e!%er ) unsaturated lactone ring

attached at 01*2 al"ha 3 "osition

E/a!"le4

S5uill %ul% glycoside

Scillaren


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E/amples'

Digitalis purpurea- Digitoxin, Digoxin

Digitalis lanata- Digoxin, lanatosides,Deslanoside

Strophanthus gratus- Ouabain


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The steroidal aglycone of the glycosides is

responsible for cardiac activity.

Sugarsprovide favorable solubility and

distribution, affect its potency and duration of

action.


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Sugar moeity

The hydro/yl group at 43= of the aglycone portion is

usually con@ugated to a monosaccharide or a

polysaccharide #ith -+,

The presence o" an O3acetyl group on a sugar greatly

affects the lipophilic character and pharmaco&inetics of

the entire glycoside.

hese sugars predominantly exist in the cardiacglycosides in the -conformation.


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Rings A-B and C-% are cis

fused, while rings B-C have a

trans fusion

characteristic

"U" shape

#o angular methyl

groups at C-+ and C-+$

0ydroxyl groups are

located at C-$, the site of

the sugar attachment, andat C-+


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Poin"! "o remem5er

Steroidal nucleus must #e present*

$b-40 group involved in glycosidic lin&age.

+


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