Combinatorial Chemistry

1. Combinatorial Chemistry Advanced Medicinal Chemistry (Pharm 5219): Section A Md. Saifuzzaman Assoc. Professor saifuzzaman17@yahoo.com Ref.: An Introduction to Medicinal Chemistry, 3rd ed. 2005, G.L.Patrick, Oxford University press

2. Combinatorial synthesis A means of producing a large number of compounds in short period of time, using a defined reaction route and a large variety of starting materials and reagents. Combinatorial chemistry is an approach providing efficient synthesis of large collection of molecules & screening of libraries of related compounds to isolate molecule of desirable property.

4. Combinatorial synthesis • Done on a very small scale • Using solid phase synthesis • Automated or semi-automated process • Each reaction in several reaction vessels at the same time and under identical condition, using different reagents in each vessel. • When single product is obtained in each vessel – parallel synthesis • When mixtures of compounds are produced – mixed synthesis

5. Why needed? M. chemistry requires – rapid synthesis of large no. of compounds. Major driving force (old)– need to find new lead compounds. At present, an explosion in no. of new drug targets developed by proteomics & genomics. With huge new targets, there is a problem of identifying function of targets and finding lead compounds interacting to them. Driving force (now) – discovery of new drug targets.

6. Why needed? To find a lead compound – lead discovery program for 100 targets & screen over 1 million compounds per year (avg. works in a pharma company). Com. chem. provides a means of producing that many compounds.

7. Combinatorial synthesis in drug discovery & drug optimization Find a target Find a lead Isolate active structure Identify structure SAR Optimize lead Combinatorial synthesis Combinatorial synthesis

8. How used? Both parallel & mixed syntheses – can be used But mixed synthesis – generate more structure & increase chance of finding a lead compound. Mixtures of compounds – produced in each reaction flask (thousands or even millions of novel structures vs few dozen by conventional means).

9. How used? Mixtures of compounds in a reaction vessel – tested for biological activity. If negative, no need to study that mixture & stored. If positive, identify which component is active compound. That saves effort of synthesizing, purifying and identifying each components of that mixture.

10. Mixed combinatorial synthesis: equivalent of nature’s chemical pool Through evolution, nature has produced a huge number & variety of chemical structures, some biologically active. Traditionally, active principles – picked up from that pool and developed. Mixed combinatorial synthesis – pools of purely synthetic structures – pick up active compounds. Diversity is less but isolating, purifying and identifying new agents is faster.

11. Parallel synthesis in SAR & drug optimization Each compound has to be tested individually. Though more compounds by mixed synthesis, time saved in producing them lost in separation & identification. Parallel synthesis is more common than mixed synthesis in Ph. Industry.

12. Advantages of Combinatorial Synthesis • Perform fewer reactions and fewer tests to identify the biological activity of a “winning” molecule • Use synthetic organic chemistry to generate many compounds in a single or parallel batch

13. Synthesis of Fruity Esters Assigned Problem Use combinatorial chemistry to synthesize an ester of an assigned scent.

14. CH3OH A1 CH3CH2OH A2 1-pentanol A3 3-methylbutanol A4 1-octanol A5 Butanoic acid C1 Propanoic acid C2 Acetic acid C3 Generation of library of molecules Mix combinations of alcohols and carboxylic acids to solve the assigned problem Possible combinations – A1C1, A1C2, A1C3……. Deconvolution of library – checking the odor of esters

15. Preparation of Hydrazones and Discovery of an Antibiotic Compound using Combinatorial techniques Synthesis of Hydrazones

16. Generation of Libraries

17. Solid phase techniques Combinatorial experiments….. Few - in solution Majority - using solid phase techniques

18. Solid phase techniques Advantages of solid phase techniques • Different starting materials - bound to separate beads – mixed together – treated with another reagent as a single experiment. Starting materials & products – still physically distinct. • Excess reagents and unbound by-products – can be removed by washing the resin. • Large excesses of reagents – can be used to drive the reactions to completion (≥ 99%). • If low loadings (≤ 0.8 mmol/g support), undesired side effects (e.g., cross-linking) can be suppressed.

19. Solid phase techniques Advantages of solid phase techniques….. • Intermediates – bound to the bead, so no need to purify. • Individual beads – separated at the end to yield individual products. • Polymeric support – regenerated & reused if appropriate cleavage conditions and suitable anchor/linker groups. • Automation possible.

20. Solid phase techniques Essential requirements for solid phase synthesis • A cross-linked insoluble polymeric support – inert to reaction conditions (e.g., a resin bead). • An anchor/linker covalently linked to resin – with a reactive functional group (i.e., substrates can attach to it). • A bond linking substance to linker – stable to reaction conditions used in synthesis. • A means of cleaving products or intermediates from linker. • Protection of functional groups not involved in synthesis.