Combinatorial chemistry

Combinatorial chemistry is to prepare libraries of very large number compounds then identify the useful compounds of the libraries.

1. Combinatorial chemistry Presented by: S.Afreen 18M71S0101 M.Pharm Pharmacology. 1

2. It is a chemical synthetic method that make possible to prepare a large number of compound in a single process. Definition : 2

3. Principle: 3 The basic principle of combinatorial chemistry is to prepare libraries of very large number compounds then identify the useful compounds of the libraries.

4. Drug discovery: 4 Therapeutic target Lead discovery Lead optimization Development candidates Drug Combinatorial chemistry

5. 5   APPROACH:     The combinatorial chemistry approach has two phases:  1. Making a library. 2. Finding the active compound.

6. 6 Conventional synthesis Combinatorial synthesis Only one compound is synthesized at a time A range of compounds are synthesized at a time Require more time Require less time More expensive Less expensive Slower lead generation Faster lead generation Strategies:

7. 7 The creation of large libraries of molecules in a short time . Medicinal chemistry can be synthesized using combinatorial techniques More opportunities to generate lead compounds. Speeds up drug discovery Advantages : Disadvantages : solve all the problems associated with drug discovery, one still needs to synthesize the right compound. There is a limit to the chemistry you can do when using solid phase synthesis.  

8. 8 TECHNIQUES :   • solid phase Technique   Solid Support Method Parallel Synthesis  Manual method  Automated Mixed combinatorial Synthesis Mixed & split Combinatorial Synthesis • Solution phase Technique

9. 9 Solid phase technique: • In solid phase combinatorial chemistry, the starting compound is attached to an insoluble resin bead, reagents are added to the solution in excess, and the resulting products can be isolated by simple filtration, which traps the beads while the excess reagent is washed away. Synthesis of peptides and most of the easily carried out on combinatorial synthesis was performed on peptides.

10. 10 The solid supports are usually composed of two parts: The core and The linker. Core--------Linker--------Start compound Three major components that are required for solid phase synthesis are: The solid support The anchor/ linker Protection and Deprotection method

11. 11 Types of solid phase  used: * Polystyrene resins * Poly acrylamide resins * Tenta Gel resins

12. 12 Linker and Anchor used in solid phase: It is a molecular unit covalently attached to the solid support via the linker. Linker is a bifunctional molecule. The linker is bound the resin is called anchor. Resin + Linker ----------> Resin----Anchor Ex: Merrifield resin Tritylchloride resin Wang resin Hydroxymethyl resin

13. 13 Protecting groups: A protecting group is reversibly attached to the functional group to convert it to a less reactive form. When the protection is no longer needed, the protecting group is cleaved and the original functionality is restored.   A large number of protecting groups were developed for use in peptide synthesis since the amino acids are multifunctional compounds. Ex : Boc Fmoc / t- Bustrategy

14. 14 Parallel synthesis :   Starting material is reacted with each building block separately . After each reaction step the product is split into ‘n’ portions before it is reacted with n new building blocks. • The identity of each structure is known.

15. 15 • Each tea bag contains beads and is labelled • Separate reactions are carried out on each tea bag. • Combine tea bags for common reactions or work up procedures. • A single product is synthesised within each tea bag. • Different products are formed in different tea bags. • Cheap and possible for any lab • Manual procedure and is not suitable for producing large. Teabag method :

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17. 17 • Automated synthesisers are available with 42, 96 or 144 reaction vessels or wells. • Use beads or pins for solid phase support • Reactions and work ups are carried out automatically. • Same synthetic route used for each vessel, but different reagents. • Different product obtained per vessel. Automated parellel synthesis:

18. 18 Mixed Combinatorial Synthesis • To use a standard synthetic route to produce a large variety of different analogues where each reaction vessel or tube contains a mixture of products. • The identities of the structures in each vessel are not known with certainty. • Useful for finding a lead compound • Capable of synthesizing large numbers of compounds quickly. • Each mixture is tested for activity as the mixture. • Inactive mixtures are stored in combinatorial libraries. • Active mixtures are studied further to identify active component.

19. 19 Mix and Split Method • In this technique, the starting material is split in ‘n’ portions, reacted with ‘n’ building blocks, and recombined in one flask. For the second step, this procedure is repeated.

20. 20 Solution phase Technique: • It is the modified reaction to accommodate a solid support . The solution phase synthesis involves conducting chemical reaction simultaneously, preferably in well-ordered sets (arrays) of reaction vessels in solution. • Solution phase combinatorial chemistry often lead to a formation of Mixture of product . • May helpful for development of Amazing Mixture

21. 21 Problems : 1. difficulty of removing unwanted material 2. purification at each step is necessary 3. other practical problem.

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