Combinatorial Chemistry and Library Design

1. Combinatorial Chemistry and Library Design Prof. K. N. RAJINI KANTH M.Pharm.,(PhD) Head, Dept. of Pharmaceutical Analysis Chalapathi Institute of Pharmaceutical Sciences Chalapathi Nagar, Lam, Guntur

2. DEFINITION • The automated synthesis of a large number of chemical variants in a short time period using a defined reaction route and a large variety of reactants • Normally carried out on small scale using solid phase synthesis and automated synthetic machines • This approach gives rise to large number of biologically screenable compounds - Combinatorial Library • Parallel synthesis • Single product formed in each reaction vessel • Useful for SAR and drug optimisation • Synthesis of mixtures • Mixtures of compounds formed in each reaction vessel • Useful for finding lead compounds

3. Swelling Starting material, reagents and solvent Linkers SOLID PHASE TECHNIQUES • Beads must be able to swell in the solvent used, and remain • stable • Most reactions occur in the bead interior

4. Linking functional group Linker Bead Linker Wang resin

5. Piperidine Deprotection Wang resin Carboxylic acid Carboxylic acid

6. 22 Parallel Synthesis Houghton’s Tea Bag Procedure • 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 teabag • Different products are formed in different teabags • Economy of effort - e.g. combining tea bags for workups • Cheap and possible for any lab • Manual procedure and is not suitable for producing large quantities of different products

7. Parallel Synthesis Automated Parallel Synthesis AUTOMATED SYNTHETIC MACHINES

8. Linker Release from solid support Peptide Merrifield resin for peptide synthesis (chloromethyl group)

9. Parallel Synthesis Automated parallel synthesis of all 27 tripeptides from 3 amino acids ETC

10. Parallel Synthesis Automated parallel synthesis of all 27 tripeptides from 3 amino acids 27 TRIPEPTIDES 27 VIALS

11. 4. Mixed Combinatorial Synthesis The Mix and Split Method Synthesis of all possible tripeptides using 3 amino acids

12. 4. Mixed Combinatorial Synthesis The Mix and Split Method

13. 4. Mixed Combinatorial Synthesis The Mix and Split Method

14. 4. Mixed Combinatorial Synthesis The Mix and Split Method MIX

15. 4. Mixed Combinatorial Synthesis The Mix and Split Method SPLIT

16. 4. Mixed Combinatorial Synthesis The Mix and Split Method

17. 4. Mixed Combinatorial Synthesis The Mix and Split Method

18. 4. Mixed Combinatorial Synthesis The Mix and Split Method

19. 4. Mixed Combinatorial Synthesis The Mix and Split Method MIX

20. 4. Mixed Combinatorial Synthesis The Mix and Split Method SPLIT

21. 4. Mixed Combinatorial Synthesis The Mix and Split Method

22. 4. Mixed Combinatorial Synthesis The Mix and Split Method

23. 4. Mixed Combinatorial Synthesis The Mix and Split Method

24. 4. Mixed Combinatorial Synthesis The Mix and Split Method No. of Tripeptides 9 9 9

25. 0 4. Mixed Combinatorial Synthesis The Mix and Split Method No. of Tripeptides 9 9 9 27 Tripeptides 3 Vials

26. 0 4. Mixed Combinatorial Synthesis The Mix and Split Method TEST MIXTURES FOR ACTIVITY

27. 0 4. Mixed Combinatorial Synthesis The Mix and Split Method Synthesise each tripeptide and test

28. 0 5. Identification of structures from mixed combinatorial synthesis • 5.1 Recursive Deconvolution • Method of identifying the active component in a mixture • Quicker than separately synthesising all possible components • Need to retain samples before each mix and split stage • Example • Consider all 27 tripeptides synthesised by the mix and split strategy • from glycine, alanine and valine

29. Mix and Split Gly Ala Val All possible dipeptides in three vessels Retain a sample from each vessel

30. Mix and Split Ala Val Gly All possible tripeptides in three vessels

31. 5. Identification of structures from mixed combinatorial synthesis 5.1 Recursive Deconvolution Mixture Inactive Mixture Inactive Mixture Active • 9 Possible tripeptides in active mixture • All end in valine • Add valine to the three retained dipeptide mixtures

32. 5. Identification of structures from mixed combinatorial synthesis 5.1 Recursive Deconvolution • Active component narrowed down to one of three possible tripeptides • Synthesise each tripeptide and test

33. 7. Combinatorial synthesis Heterocyclic synthesis - 1,4-benzodiazepines Drawback: Final product must contain X= OH or CO2H

34. 7. Combinatorial synthesis Heterocyclic synthesis - improved synthesis of benzodiazepines

35. 8. Planning a Combinatorial Synthesis • To generate a large number of compounds • To generate a diverse range of compounds • Increase chances of finding a lead compound to fit a binding site • Synthesis based on producing a molecular core or scaffold with functionality attached Target molecules should obey Lipinski’s ‘Rule of Five’ The Lipinski "Rule of Five" states that compounds are likely to have good absorption and permeation in biological systems and are more likely to be successful drug candidates if they meet the following criteria: five or fewer hydrogen-bond donors ten (2 x 5) or fewer hydrogen-bond acceptors molecular weight less than or equal to 500 calculated logP less than or equal to 5

36. References: 1.