history 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 In 1982 Hungarian Patent Literature published Arpad Furka ,extend the Merrifield ‘s concept In 1984 Merrifield got Nobel prize In 1963 Merrifield introduce the concept
What is combinatorial chemistry ? Parallel generation of all possible combination of substituents or components in a synthetic experiments.
Difference Between Traditional Synthesis & Combinatorial Synthesis :1 Reaction Many a times simpler Not so simple2 Extreme condition i.e. at Avoid May possible to use extreme temp./ pressure3 Use of highly Caustic Generally avoid Possible to use reagent4 Use of Inert atmosphere Avoid May use5 Multistep Reaction Avoid Possible6 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 Ser Ala Val Phe Combine Phe Ala Val Gly Ser Gly Ser Gly Val Gly Phe Phe Ala Gly Gly Gly Gly
Parallel synthesisWhat is the basic idea behind parallel synthesis ? The process where a single reaction product is produced in each reaction vessel. Approach Houghtons 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-MixtureProblems : # 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 Solution phase technique Technique1 Reagent Excess Optimum (unless purification done)2 Purification Easy Can be difficult3 Automation Easy Difficult4 Reaction Suitable for few Suitable for any organic substance reaction5 Scale-up Expensive Easy & inexpensive6 Dependence of Mainly on - Time reaction development - 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 librariese.g.- 1,4-Benzodiazepine All common reaction ,moisture sensitive & organometallic reactionse.g. Aldol reaction ,Dibal Reduction, Wittig reaction etc.
Example of lead compounds obtained by combinatorial chemistrySr. No. Source Target Mechanism1 Merck HIV-1 Integrase Block viral integration2 Smith-Kline Beecham Human 5-HT 6 Antagonist, Serotonin cognitive Receptor disorders3 Pfizer Farnesyl Inhibition transferase4 Park Davis KDO-8-P Inhibition, Synthetase Antibacterial .
Miniaturization Dynamic combinatorial chemistry chemoinformatics Use of advancedTargeted & diversified software & robotics libraries Agro-Chemical Computational sector QSPR chemistry Advances in solution phase & Solid phase organic synthesis QSAR
References 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. 289-318Gareth 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.