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Published by Rinta Moon
combinatorial synthesis and traditional synthesis
chemical diversity and library design
application and limitation
recent and future prospect
combinatorial synthesis and traditional synthesis
chemical diversity and library design
application and limitation
recent and future prospect

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Published by: Rinta Moon on Dec 08, 2013
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Combinatorial chemistry

Guided by : Mr. R.T.Lohiya
Presented by : Mr. Bhaskar H. Borkar

Department of pharmaceutical chemistry ,S.K.B. college of pharmacy , New – Kamptee .

Introduction Background Basic concepts Combinatorial synthesis Combinatorial synthesis & Traditional synthesis Techniques Isolation/Detection/Purification /Analysis Chemical Diversity & Liabrary Design Application & limitation Recent & Future Prospect References


Continuous improvement in various field In 1992 Bunin & Ellman demonstrate the synthesis of 1,4-Benzodiazepine
Introduce the method of generating small Non-peptide molecule i.e.Peptoid
First combinatorial chemistry experiment

were applied to the study of Epitope


Hungarian Patent Literature published

Arpad Furka ,extend the Merrifield ‘s concept In

1984 Merrifield got Nobel prize


1963 Merrifield introduce the concept

What is combinatorial chemistry ?
 Parallel generation of all possible combination of substituent's or components in a synthetic experiments.

Role of combinatorial chemistry

Difference Between Traditional Synthesis & Combinatorial Synthesis :
1 Reaction Many a times simpler Not so simple


Extreme condition i.e. at extreme temp./ pressure
Use of highly Caustic reagent Use of Inert atmosphere


May possible to use

3 4

Generally avoid Avoid

Possible to use May use

5 6

Multistep Reaction Yield of compound



Gives chemical library Gives single compound

Techniques used in the combinatorial synthesis :

 solid phase Technique
 Solid Support Method  Parallel Synthesis
 Manual method  Automated

 Mixed combinatorial Synthesis  Mixed & split Combinatorial Synthesis

 Solution phase Technique

Solid phase technique :

 The solid support e.g. Cross-linked polystyrene Bead

 The anchor / linker e.g. Polystyrene resin , Tentagel resin , Polyacrylamide resin, Glass & ceramic beads .

 Mixed combinatorial synthesis :
Gly Ala Val Combine Ala Gly Ser Phe



Ser Val Ala Gly Gly Phe Gly Gly

Gly Phe


 Split & Mix Synthesis :

 Parallel synthesis What is the basic idea behind parallel synthesis ? The process where a single reaction product is produced in each reaction vessel.
Approach  Houghton's Tea bag Procedure  Automated Parallel Synthesis

Solution phase combinatorial chemistry
 It is the modified reaction to accommodate a solid support .  Solution phase combinatorial chemistry often lead to a formation of Mixture of product .  May helpful for development of Amazing-Mixture

Problems : # difficulty of removing unwanted material # purification at each step is necessary # other practical problem

Comparison between solid phase & solution phase chemistry :

Comparison between solid phase & solution phase technique :
Sr. No. Parameter Solid Phase technique Solution phase Technique




Optimum (unless purification done)
Can be difficult Difficult Suitable for any organic reaction Easy & inexpensive Time

2 3 4 5 6

Purification Automation Reaction Scale-up Dependence of reaction development

Easy Easy Suitable for few substance Expensive Mainly on - support - Linkers

Detection / Purification / Analysis

 Quantities of analyzed are very small  Nondestructive / Allow recovery  Rapid / Parallel analysis
 Use hyphenated analytical technique e.g. HPLC-MS  Chromatography  Use IR / FTIR (computerized method)  Use NMR / 2D-NMR / HPLC-NMR / CE-NMR  MS / EI / MALDI-TOF / SIMS  Use HPLC  Supercritical Fluid Chromatography

 Isolation i.e. Deconvlution - micromanipulation - recursive deconvolution - sequential release  Structural determination of the active compd. - Tagging - Encoded sheets - Photolithography

Chemical diversity & Libraries :

It has been suggested that effectiveness of combinatorial chemistry could be improved by enhancing the chemical diversity of screening libraries .
Two more important features : - Chirality - Rigidity

Limitation of combinatorial chemistry

 How many beads will be required for combinatorial synthesis ?
 Probability of finding sample ………….?

 Requirement of practical details of weight & volume.

Example of combinatorial chemistry

 Early work carried on peptides  Next work done on peptoid  Now researcher get concentrated on the heterocyclic combinatorial libraries e.g.- 1,4-Benzodiazepine  All common reaction ,moisture sensitive & organometallic reactions e.g. Aldol reaction ,Dibal Reduction, Wittig reaction etc.

Example of lead compounds obtained by combinatorial chemistry
Sr. No. Source 1 Merck Target Mechanism

HIV-1 Integrase Block viral integration Human 5-HT 6 Serotonin Receptor Farnesyl transferase KDO-8-P Synthetase Antagonist, cognitive disorders Inhibition Inhibition, Antibacterial .


Smith-Kline Beecham

3 4

Pfizer Park Davis

Miniaturization Dynamic combinatorial chemistry chemoinformatics

Targeted & diversified libraries

Use of advanced software & robotics

Agro-Chemical sector Advances in solution phase & Solid phase organic synthesis

Computational chemistry



 Douglas R Henry ; Wilson & Gisvold‘s Textbook of Organic Medicinal chemistry ; 11th edition ;Lippincott William & Wilkins Publication ; 2004 ;Page No. 43-63 .  Grahm L. Patrick ; Introduction To Medicinal Chemistry ; 2nd Edition ; Oxford publication ; 2003 ;Page No. 289-318  Gareth Thomas ; Medicinal Chemistry –An Introduction ; Willey publication ; 2000 ; Page No. 69-90 .  R.B.Silverman ; Organic chemistry of drug design & Drug Action ; 2nd Edition ;Elsevier publication ;2004 ; Page No.35-43 .  www.netsci.org/science/Combichem/feature02.html  www.biotech.nature.com ; NATURE BIOTECHNOLOGY ; Vol 18 ; Supplement 2000.

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