Structure activity relationship 6
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Transcript of 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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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