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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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