structure activity relationship 6

STRUCTURE ACTIVITY

RELATIONSHIP

Abdul Samad

Dr. Syed Badshah

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Structure

Activity

SAR (Discussion/Elaboration)

Contents

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3

Crude drug Structure Ligand bindingReceptor

Biological

response

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CHEMICAL STRUCTURE

A chemical structure includes molecular geometry,

electronic structure, and crystal structure of a molecule.

BIOLOGICAL ACTIVITY

Biological activity is an expression describing the beneficial

or adverse effects of a drug on living matter.

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STRUCTURE ACTIVITY RELATIONSHIP

The relationship between the chemical or 3D

structure of a molecule and its biological activity.

Enables the determination of the chemical groups

responsible for evoking a target biological effect in

the organism.

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WHY SAR Exist?

• The interaction of the drug molecule with protein depends

on its chemical structure

NEED OF SAR STUDY

• A study of the structure–activity relationship is mainly

done by lead molecule.

• It is used to determine pharmacophore, unwanted side

effects

• To develop a new drug that has increased activity.

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Cont.…..

• To determine some different activity from an

existing drug

• To fewer unwanted side effects

• To know the changes in pharmacological properties

by performing minor changes in the drug molecule

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SAR (DISCUSSION/ELABORATION)

FFFFFFFFFFFFFFFFFollowing

cALKALOIDSCFLAVONOIDS TERPENOIDS

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TAXOL CPT

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Camptothecin

(CPT)

WALL & WANI in

early Sixties

Camptotheca

cuminata,Tree of

Joy, Love

Quinolino

alkaloid

Pentacyclic

ring

structure

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STRUCTURE OF CPT WITH IUPAC

NAME

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A B C

D

E

Rings A–D are essential for activity. Saturation of ring B< activity

necessary for activity

essential for activity, S N

inactive

D-ring pyridone is required for anti

tumor activity.

Modifications in rings A, B are well tolerated

The stereochemistry at C-20 is very crucial as

20(S) hydroxyl is active, 20(R) inactive

modifications at the C , D rings led

to complete loss of cytotoxicity.

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Modification in rings A,B

Topotecan

Irinotecan

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Modification in rings C,D

In general, modifications at the C and D rings of

camptothecin led to complete loss of cytotoxicity.

If we see these rings, the only positions available

for modifications are C-5, C-14 and C-17. Several

derivatives have been reported either with less

activity or with loss of activity.

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Modification in ring E

The α- hydroxyl lactone system of ring E has been

found to be important for the inhibition of the

topoisomerase enzyme as well as for in vivo

potency

Derivatives having a lactam group instead of a

lactone, were devoid of topoisomerase inhibitor

activity.

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TAXOL

Taxol, paclitaxel, trade name taxol,

by Dr. WALL and Dr. WANI

Complex

polyoxygenated

diterpenoid

Pacific yew, Taxus

brevifolia

basic [9.3.1.0]

Pentadecane, tetracyclic

ring system.

N-benzoyl-b-phenyl

isoserine side chain, at

the C-13 hydroxyl as an

ester linkage.

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STRUCTURE OF TAXOL WITH IUPAC NAME

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Oxitane ring essential

Ester, Amino

ester,epimer,deoxy =

active

Reduction enhance activityRemoval of acetyl < activity

Phenyl isoserine chain essential for activity

N-acyl group, required

Aryl group, essential

Free OH active in both(in vivo, in vitro)

Ester only in vivo

The C-3’aryl group is required for better

activity, methyl group, activity is reduced19-

fold.

northern and southern hemispheres.

modifications in the southern hemisphere are strictly forbidden

while in the northern hemisphere are allowed

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C-13 SIDE CHAIN

C-13 side chain is essentially required for anticancer

activity. The C-2’-hydroxyl is important for activity.

When this hydroxyl is protected, activity is reduced to a

great extent and if the protection is made with a labile

group it shows similar activity in vivo, while no activity is

shown in in vitro testing

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FLAVONOIDS

QUERCETIN

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The main structural features of flavonoids required forefficient radical scavenging could be summarized as

i. An ortho-dihydroxy (catechol) structure in the B

ring, for electron delocalization

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2,3-double bond in conjugation with a 4-oxo function in

the C ring provides electron delocalization from the B ring

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Hydroxyl groups at positions 3 and 5 provide hydrogen

bonding to the Oxo group

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THANK YOU