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Combinatorial Chemistry

Combinatorial chemistry utilizes efficient synthetic methods to produce a vast number of compounds in a single process, enhancing drug discovery by allowing for the testing of numerous analogues simultaneously. Applications include lead optimization, drug development, and the synthesis of compound libraries, although it faces challenges such as reaction speed, cost, and stability issues with solid supports. Recent advancements in parallel synthesis and automated techniques highlight the significant growth and potential of combinatorial approaches in medicinal chemistry.

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Ms. Pradnya Gondane Assistant Professor Gurunanak College of Pharmacy, Nagpur
Introduction • Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compounds are then tested for pharmacological activity. • The key of combinatorial chemistry is that a large range of analogues is synthesised using the same reaction conditions, the same reaction vessels. In this way, the chemist can synthesise many hundreds or thousands of compounds in one time instead of preparing only a few by simple methodology. • The collection of these finally synthesized compounds is referred to as a “combinatorial library”.
Traditional synthesis Combinatorial synthesis A1 A2 An B1 B2 Bn A(1-n)B(1-n)
Combinatorial library Def: Collection of finally synthesized compounds Size: depends on the number of building blocks used per reaction and the number of reaction steps, in which a new building block is introduced Typical: 102 up to 105 compounds
Application: • Applications of combinatorial chemistry are very wide. Scientists use combinatorial chemistry to create large populations of molecules that can be screened efficiently. • By producing larger, more diverse compound libraries, companies increase the probability that they will find novel compounds of significant therapeutic and commercial value. • Provides a stimulus for robot-controlled and immobilization strategies that allow high-thrughput and multiple parallel approaches to drug discovery.
Applications continued • Finding the right combination of drug molecules. • It provides fresh and promising leads for medicinal chemistry. • Synthesis of small molecular libraries. • Application of antibody libraries obtained. • Development of enzyme linked inhibitors. • As a tool for lead optimization. • Quantitative and qualitative characterization of drug database.
Advantages • Easily removed from reactions by filtration. • Excess reagents can be used to drive reactions to completion. • Economical, environmentally sound and efficient. • Easy to handle. • Safe to handle. • Very good selectivity.
Advantages: Fast Combinatorial approach can give rise to million of compound in same time as it will take to produce one compound by traditional method of synthesis . Economical A negative result of mixture saves the effort of synthesis, purification & identification of each compound Easy Isolation, purification & identification of active molecule from combinatorial library is relatively easy. Drug Discovery Mixed Combinatorial synthesis produces chemical pool. Probability of finding a molecule in a random screening process is proportional to the number of molecules subjected to the screening process Drug Optimization Parallel synthesis produces analogues with slight differences which is required for lead optimization
Disadvantages: 1. Some reagents may not interact with solid support. 2. Ability of recycled reagents is not assured on solid support 3. Due to diffusional constraints reactions may run more slowly. 4. Can be very expensive to prepare specific polymeric support materials. 5. Under harsh reaction conditions, stability of the support material can be poor. 6. Sometimes side reactions with polymer support. 7. Efficiency is highly affected by compound's size, solubility and function group. 8. Compounds produced tend to be Achiral of Racemic mixture.
Solid Phase synthesis • In this method the compound library is synthesized on solid phase such as resin bead, pins or chips etc. • It was first introduced by Merrifield in the year 1963 for which he was awarded Nobel prize. • Merrifield developed a series of chemical reactions that can be used to synthesise proteins. The intended carboxy terminal amino acid is anchored to a solid support. Then, the next amino acid is coupled to the first one. In order to prevent further chain growth at this point, the amino acid, which is added, has its amino group blocked. After the coupling step, the block is removed from the primary amino group and the coupling reaction is repeated with the next amino acid. The process continues until the peptide or protein is completed. Then, the molecule is cleaved from the solid support and any groups protecting amino acid side chains are removed. Finally, the peptide or protein is purified to remove partial unwanted products.
1. SOLID PHASE TECHNIQUES • Reactants are bound to a polymeric surface and modified whilst still attached. Final product is released at the end of the synthesis • Specific reactants can be bound to specific beads • Beads can be mixed and reacted in the same reaction vessel • Products formed are distinctive for each bead and physically distinct • Excess reagents can be used to drive reactions to completion • Excess reagents and by products are easily removed • Reaction intermediates are attached to bead and do not need to be isolated and purified • Individual beads can be separated to isolate individual products • Polymeric support can be regenerated and re-used after cleaving the product • Automation is possible
The use of solid support for organic synthesis relies on three interconnected requirements: 1) A cross linked, insoluble polymeric material that is inert to the condition of synthesis 2) Some means of linking the substrate to this solid phase that permits selective cleavage of some or all of the product from the solid support during synthesis for analysis of the extent of reaction(s), and ultimately to give the final product of interest 3) A chemical protection strategy to allow selective protection and deprotection of reactive groups.
Resin Linker Substrate Reagent Product Resin
Cross linked Polystyrene resins, Polyacrylamide resins, Polyamide resins, Tenta gel Carboxylic acid linkers, Wang linker, carboxamide linker, Carbamate linkers FMOC(Fluro methoxy carbonyl benzyl ester), TBOC (Tertiary butyloxy carbonyl) Solid support Linkers Protecting groups
Starting material, reagents and solvent Swelling Linkers 1. SOLID PHASE TECHNIQUES • Beads must be able to swell in the solvent used, and remain stable • Most reactions occur in the bead interior Resin bead
1. SOLID PHASE TECHNIQUES Anchor or linker • A molecular moiety which is covalently attached to the solid support, and which contains a reactive functional group • Allows attachment of the first reactant • The link must be stable to the reaction conditions in the synthesis but easily cleaved to release the final compound • Different linkers are available depending on the functional group to be attached and the desired functional group on the product • Resins are named to define the linker e.g. Merrifield, Wang, Rink
Solid phase synthesis: protecting groups  A few protecting groups used in solid phase synthesis.  For amines.  Boc ( t-butoxycarbonyl )  Fmoc (9-fluorenylmetoxy carbonyl)  Tmsec (2 [ trimethylsilyl ] ethoxycarbonyl)  For carboxylic acids.  Tert Bu ester(t-butyl ester)  Fm ester(9-fluronyl methyl ester)  Tmse ester(2 [trimethylsilyl] ethyl) 19 19
Deprotection O aa1aa2aa3 O aan NH2 Merrifield resin for peptide synthesis (chloromethyl group) O O R NHBoc H O O R NH2 H HO2C NHBoc R2 H coupling O O R NH H O NHBoc R2 H = resin bead Cl HO2C NHBoc R H + Linker HF OH aa1aa2aa3 aanHO2C NH2 Peptide Release from solid support
equipment for Solid Phase Peptide Synthesis
2. Parallel Synthesis Aims: • To use a standard synthetic route to produce a range of analogues, with a different analogue in each reaction vessel, tube or well • The identity of each structure is known • Useful for producing a range of analogues for SAR or drug optimisation
Parallel synthesis
• 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 2. Parallel Synthesis 2.1 Houghton’s Tea Bag Procedure 22
2. Parallel Synthesis Automated parallel synthesis Wells • 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
ETC 3. Parallel Synthesis Automated parallel synthesis of all 27 tri peptides from 3 amino acids
27 TRIPEPTIDES 27 VIALS 2. Parallel Synthesis Automated parallel synthesis of all 27 tripeptides from 3 amino acids
3. Mixed Combinatorial Synthesis Aims • 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 synthesising 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
Synthesis of all possible tri peptides using 3 amino acids 3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
MIX 3. Mixed Combinatorial Synthesis The Mix and Split Method
SPLIT 3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
MIX 3. Mixed Combinatorial Synthesis The Mix and Split Method
SPLIT 3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
3. Mixed Combinatorial Synthesis The Mix and Split Method
No. of Tripeptides 9 9 9 3. Mixed Combinatorial Synthesis The Mix and Split Method
No. of Tripeptides 9 9 9 27 Tripeptides 3 Vials 3. Mixed Combinatorial Synthesis The Mix and Split Method
TEST MIXTURES FOR ACTIVITY 3. Mixed Combinatorial Synthesis The Mix and Split Method
Synthesise each tripeptide and test 3. Mixed Combinatorial Synthesis The Mix and Split Method
20 AMINO ACIDS HEXAPEPTIDES 34 MILLION PRODUCTS (1,889,568 hexapeptides / vial) etc. 3. Mixed Combinatorial Synthesis The Mix and Split Method
Gl ycine (Gl y) Alanine (Ala) Phenylal anine (Phe) Valine (Val) Serine (Ser) 25 separate experi ments Gl y-Gl y Gl y-Ala Gl y-Phe Gl y-Val Gl y-Ser Ala-Gly Ala-Ala Ala-Phe Ala-Val Ala-Ser Phe-Gl y Phe-Ala Phe-Phe Phe-Val Phe-Ser Val-Gly Val-Ala Val-Phe Val-Val Val-Ser Ser-Gly Ser-Ala Ser-Phe Ser-Val Ser-Ser 3. Mixed Combinatorial Synthesis The Mix and Split Method Combinatorial procedure involves five separate syntheses using a mix and split strategy Example - Synthesis of all possible dipeptides using 5 amino acids •Standard methods would involve 25 separate syntheses
combi ne Gly Ala Phe Val Ser Gly Ala Phe Val Ser + + + + + Gly Ala Phe Val Ser Split Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Gly Gly Gly Gly Gly Ala Phe Val Ser Ser Ser Ser Ser Ser Gly Ala Phe Val Ser Ala Ala Ala Ala Ala Gly Ala Phe Val Ser Val Val Val Val Val Gly Ala Phe Val Ser Phe Phe Phe Phe Phe
Equipment for mixed combinatorial synthesis:
Mix and split synthesis Parallel synthesis
Solution phase synthesis • This method is carried out without the aid of solid support. Substrate Reagent Product Excess reagent Scavenger Product Filter Product Scavenger + excess reagent
4.Solution phase synthesis
4 component UGI reaction:
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 5. Identification of structures from mixed combinatorial synthesis
Gly Ala Val Gly Ala Val Gly Ala Val Gly Ala Val Gly Ala Val Gly Ala Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Mix and Split All possible di peptides in three vessels Retain a sample from each vessel
Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Val Val Val Val Val Val Val Val Mix and Split All possible tripeptides in three vessels
5. Identification of structures from mixed combinatorial synthesis Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Val Val Val Val Val Val Val Val Mixture Inactive Mixture Inactive Mixture Active • 9 Possible tripeptides in active mixture • All end in valine • Add valine to the three retained dipeptide mixtures 5.1 Recursive Deconvolution
Gly Ala Val Gly Ala Val Gly Ala Val Gly Gly Gly Ala Ala Ala Val Val Val Val Val Val Gly Ala Val Gly Ala Val Gly Ala Val Gly Gly Gly Ala Ala Ala Val Val Val Val Val Val Val Val Val Val Val Val Active • Active component narrowed down to one of three possible tripeptides • Synthesise each tripeptide and test 5. Identification of structures from mixed combinatorial synthesis 5.1 Recursive Deconvolution
NH O NH2 HN O O HN MeOS SOMe O H2N H N H H Lysine Tryptophan NH2 NH2 5.2 Tagging: SCAL = Safety CAtch Linker 5. Identification of structures from mixed combinatorial synthesis
NH2 NH2 RCHBrCO2H Step 1 NH2 NH O R Br amino acid(aa 1) Tag 1 HN NH O R Br aa1 NH2 R'NH2 Step 2 HN NH O R NHR' aa1 NH2 amino acid(aa 2) Tag 2 HN NH O R NHR' aa1 aa2 NH2 R"COCl Step 3 HN NH O R NR'COR" aa1 aa2 NH2 amino acid(aa 3) Tag 3 HN NH O R NR'COR" aa1 aa2 aa3 NH2 5.2 Tagging Example
N H X N H X N H X N H X N H X N H XN H XN H XN H XN H XN H X N H XN H XN H XN H XN H XN H X 6. Identification of structures from combinatorial synthesis 6.2 Photolithography - example N H XN H XN H XN H XN H XN H X M A S K 1 Mask LIGHT LIGHT N H XN H XN H XN H X N H XN H XN H XN H XN H XN H X N H X C O 2 H coupling N H X N H X N H X N H X N H X N H X N H XN H X N H X N H 2 N H 2 N H 2 N H XN H XN H XN H 2N H 2N H X N H XN H XN H XN H XN H XN H X Deprotection
Y Y Y repeat 6. Identification of structures from combinatorial synthesis 6.2 Photolithography - example Y amino acids O M e O M eO O 2 N O X= Nitroveratryloxycarbonyl fluorescent tag Target receptor Y
SEPARATIONAND ANALYSISOF COMBINATORIAL LIBRARIES Separation and analysis of combinatorial libraries places a high demand on existing analytical techniques because The quantities to be analysed are very small The analysis should be non destructive and allow the recovery of the product The methods must be suitable for rapid parallel analysis
HPLC HPLC-MS IR spectrophotometer Instruments used for analysis
Screening Screening is the process performed to identify the biologically active compound among all the compounds synthesised. The most commonly used screening methods in combinatorial chemistry are 1. Virtual screening 2. High throughput screening
Virtual screening Virtual screening refers to the use of computers to predict whether a compound will show a desired activity or not on the basis of its two dimensional and three dimensional structure.
High-throughput screening(HTS) HTS involves the process of finding an active compound against a chosen target using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-throughput screening allows a researcher to quickly conduct millions of chemical, genetic, or pharmacological tests. The results of these experiments provide starting points for drug design and for understanding the interaction or role of a particular biochemical process in biology.
Assay plate preparation Reaction observation Automation systems Hit selection Experimental design and data analysis Quality control Steps involved in HTS
Microtiter plates HTS robotic arm
Conclusion The last ten years has seen an explosion in the exploration and adoption of combinatorial techniques. Indeed, it is difficult to identify any other topic in chemistry that has ever caught the imagination of chemists with such fervour. Combinatorial chemistry as a technique for the rapid synthesis of drug-like compounds will continue to make a major impact on the way drug molecules are discovered. For pharmaceutical chemists at least the reason for this change is not hard to fathom. 20 years ago the market for pharmaceuticals was growing at around 10% per annum but more recently the rate of the market growth as decline. At the same time, cost constraints on pharmaceutical research have forced the investigation of methods that offer higher productivity at lower expenses. The belief that combinatorial chemistry will allow the productive and cost-efficient generation of both compounds and drug molecules has fuelled enormous investment in this area. Combinatorial chemistry as a technique for the rapid synthesis of drug-like compounds will continue to make a major impact on the way drug molecules are discovered.
Combinatorial Chemistry

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Combinatorial Chemistry

  • 1.
    Ms. Pradnya Gondane AssistantProfessor Gurunanak College of Pharmacy, Nagpur
  • 2.
    Introduction • Combinatorial chemistrycomprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compounds are then tested for pharmacological activity. • The key of combinatorial chemistry is that a large range of analogues is synthesised using the same reaction conditions, the same reaction vessels. In this way, the chemist can synthesise many hundreds or thousands of compounds in one time instead of preparing only a few by simple methodology. • The collection of these finally synthesized compounds is referred to as a “combinatorial library”.
  • 3.
    Traditional synthesis Combinatorialsynthesis A1 A2 An B1 B2 Bn A(1-n)B(1-n)
  • 4.
    Combinatorial library Def: Collectionof finally synthesized compounds Size: depends on the number of building blocks used per reaction and the number of reaction steps, in which a new building block is introduced Typical: 102 up to 105 compounds
  • 6.
    Application: • Applications ofcombinatorial chemistry are very wide. Scientists use combinatorial chemistry to create large populations of molecules that can be screened efficiently. • By producing larger, more diverse compound libraries, companies increase the probability that they will find novel compounds of significant therapeutic and commercial value. • Provides a stimulus for robot-controlled and immobilization strategies that allow high-thrughput and multiple parallel approaches to drug discovery.
  • 7.
    Applications continued • Findingthe right combination of drug molecules. • It provides fresh and promising leads for medicinal chemistry. • Synthesis of small molecular libraries. • Application of antibody libraries obtained. • Development of enzyme linked inhibitors. • As a tool for lead optimization. • Quantitative and qualitative characterization of drug database.
  • 8.
    Advantages • Easily removedfrom reactions by filtration. • Excess reagents can be used to drive reactions to completion. • Economical, environmentally sound and efficient. • Easy to handle. • Safe to handle. • Very good selectivity.
  • 9.
    Advantages: Fast Combinatorial approach cangive rise to million of compound in same time as it will take to produce one compound by traditional method of synthesis . Economical A negative result of mixture saves the effort of synthesis, purification & identification of each compound Easy Isolation, purification & identification of active molecule from combinatorial library is relatively easy. Drug Discovery Mixed Combinatorial synthesis produces chemical pool. Probability of finding a molecule in a random screening process is proportional to the number of molecules subjected to the screening process Drug Optimization Parallel synthesis produces analogues with slight differences which is required for lead optimization
  • 10.
    Disadvantages: 1. Some reagentsmay not interact with solid support. 2. Ability of recycled reagents is not assured on solid support 3. Due to diffusional constraints reactions may run more slowly. 4. Can be very expensive to prepare specific polymeric support materials. 5. Under harsh reaction conditions, stability of the support material can be poor. 6. Sometimes side reactions with polymer support. 7. Efficiency is highly affected by compound's size, solubility and function group. 8. Compounds produced tend to be Achiral of Racemic mixture.
  • 11.
    Solid Phase synthesis •In this method the compound library is synthesized on solid phase such as resin bead, pins or chips etc. • It was first introduced by Merrifield in the year 1963 for which he was awarded Nobel prize. • Merrifield developed a series of chemical reactions that can be used to synthesise proteins. The intended carboxy terminal amino acid is anchored to a solid support. Then, the next amino acid is coupled to the first one. In order to prevent further chain growth at this point, the amino acid, which is added, has its amino group blocked. After the coupling step, the block is removed from the primary amino group and the coupling reaction is repeated with the next amino acid. The process continues until the peptide or protein is completed. Then, the molecule is cleaved from the solid support and any groups protecting amino acid side chains are removed. Finally, the peptide or protein is purified to remove partial unwanted products.
  • 12.
    1. SOLID PHASETECHNIQUES • Reactants are bound to a polymeric surface and modified whilst still attached. Final product is released at the end of the synthesis • Specific reactants can be bound to specific beads • Beads can be mixed and reacted in the same reaction vessel • Products formed are distinctive for each bead and physically distinct • Excess reagents can be used to drive reactions to completion • Excess reagents and by products are easily removed • Reaction intermediates are attached to bead and do not need to be isolated and purified • Individual beads can be separated to isolate individual products • Polymeric support can be regenerated and re-used after cleaving the product • Automation is possible
  • 13.
    The use ofsolid support for organic synthesis relies on three interconnected requirements: 1) A cross linked, insoluble polymeric material that is inert to the condition of synthesis 2) Some means of linking the substrate to this solid phase that permits selective cleavage of some or all of the product from the solid support during synthesis for analysis of the extent of reaction(s), and ultimately to give the final product of interest 3) A chemical protection strategy to allow selective protection and deprotection of reactive groups.
  • 14.
  • 15.
    Cross linked Polystyreneresins, Polyacrylamide resins, Polyamide resins, Tenta gel Carboxylic acid linkers, Wang linker, carboxamide linker, Carbamate linkers FMOC(Fluro methoxy carbonyl benzyl ester), TBOC (Tertiary butyloxy carbonyl) Solid support Linkers Protecting groups
  • 16.
    Starting material, reagents andsolvent Swelling Linkers 1. SOLID PHASE TECHNIQUES • Beads must be able to swell in the solvent used, and remain stable • Most reactions occur in the bead interior Resin bead
  • 17.
    1. SOLID PHASETECHNIQUES Anchor or linker • A molecular moiety which is covalently attached to the solid support, and which contains a reactive functional group • Allows attachment of the first reactant • The link must be stable to the reaction conditions in the synthesis but easily cleaved to release the final compound • Different linkers are available depending on the functional group to be attached and the desired functional group on the product • Resins are named to define the linker e.g. Merrifield, Wang, Rink
  • 19.
    Solid phase synthesis:protecting groups  A few protecting groups used in solid phase synthesis.  For amines.  Boc ( t-butoxycarbonyl )  Fmoc (9-fluorenylmetoxy carbonyl)  Tmsec (2 [ trimethylsilyl ] ethoxycarbonyl)  For carboxylic acids.  Tert Bu ester(t-butyl ester)  Fm ester(9-fluronyl methyl ester)  Tmse ester(2 [trimethylsilyl] ethyl) 19 19
  • 20.
    Deprotection O aa1aa2aa3 O aan NH2 Merrifield resinfor peptide synthesis (chloromethyl group) O O R NHBoc H O O R NH2 H HO2C NHBoc R2 H coupling O O R NH H O NHBoc R2 H = resin bead Cl HO2C NHBoc R H + Linker HF OH aa1aa2aa3 aanHO2C NH2 Peptide Release from solid support
  • 21.
    equipment for SolidPhase Peptide Synthesis
  • 22.
    2. Parallel Synthesis Aims: •To use a standard synthetic route to produce a range of analogues, with a different analogue in each reaction vessel, tube or well • The identity of each structure is known • Useful for producing a range of analogues for SAR or drug optimisation
  • 23.
  • 24.
    • Each teabag 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 2. Parallel Synthesis 2.1 Houghton’s Tea Bag Procedure 22
  • 25.
    2. Parallel Synthesis Automatedparallel synthesis Wells • 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
  • 26.
    ETC 3. Parallel Synthesis Automatedparallel synthesis of all 27 tri peptides from 3 amino acids
  • 27.
    27 TRIPEPTIDES 27 VIALS 2.Parallel Synthesis Automated parallel synthesis of all 27 tripeptides from 3 amino acids
  • 28.
    3. Mixed CombinatorialSynthesis Aims • 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 synthesising 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
  • 29.
    Synthesis of allpossible tri peptides using 3 amino acids 3. Mixed Combinatorial Synthesis The Mix and Split Method
  • 30.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 31.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 32.
    MIX 3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 33.
    SPLIT 3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 34.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 35.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 36.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 37.
    MIX 3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 38.
    SPLIT 3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 39.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 40.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 41.
    3. Mixed CombinatorialSynthesis The Mix and Split Method
  • 42.
    No. of Tripeptides 9 99 3. Mixed Combinatorial Synthesis The Mix and Split Method
  • 43.
    No. of Tripeptides 9 99 27 Tripeptides 3 Vials 3. Mixed Combinatorial Synthesis The Mix and Split Method
  • 44.
    TEST MIXTURES FORACTIVITY 3. Mixed Combinatorial Synthesis The Mix and Split Method
  • 45.
    Synthesise each tripeptideand test 3. Mixed Combinatorial Synthesis The Mix and Split Method
  • 46.
    20 AMINO ACIDSHEXAPEPTIDES 34 MILLION PRODUCTS (1,889,568 hexapeptides / vial) etc. 3. Mixed Combinatorial Synthesis The Mix and Split Method
  • 47.
    Gl ycine (Gly) Alanine (Ala) Phenylal anine (Phe) Valine (Val) Serine (Ser) 25 separate experi ments Gl y-Gl y Gl y-Ala Gl y-Phe Gl y-Val Gl y-Ser Ala-Gly Ala-Ala Ala-Phe Ala-Val Ala-Ser Phe-Gl y Phe-Ala Phe-Phe Phe-Val Phe-Ser Val-Gly Val-Ala Val-Phe Val-Val Val-Ser Ser-Gly Ser-Ala Ser-Phe Ser-Val Ser-Ser 3. Mixed Combinatorial Synthesis The Mix and Split Method Combinatorial procedure involves five separate syntheses using a mix and split strategy Example - Synthesis of all possible dipeptides using 5 amino acids •Standard methods would involve 25 separate syntheses
  • 49.
    combi ne Gly Ala Phe Val Ser Gly Ala Phe Val Ser + + + + + Gly Ala Phe Val Ser Split Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly Ala Phe Val Ser Gly AlaPhe Val Ser Gly Ala Phe Val Ser Gly Gly Gly Gly Gly Gly Ala Phe Val Ser Ser Ser Ser Ser Ser Gly Ala Phe Val Ser Ala Ala Ala Ala Ala Gly Ala Phe Val Ser Val Val Val Val Val Gly Ala Phe Val Ser Phe Phe Phe Phe Phe
  • 50.
    Equipment for mixedcombinatorial synthesis:
  • 51.
    Mix and splitsynthesis Parallel synthesis
  • 52.
    Solution phase synthesis •This method is carried out without the aid of solid support. Substrate Reagent Product Excess reagent Scavenger Product Filter Product Scavenger + excess reagent
  • 53.
  • 56.
    4 component UGIreaction:
  • 57.
    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 5. Identification of structures from mixed combinatorial synthesis
  • 58.
    Gly Ala Val Gly Ala Val Gly Ala Val Gly Ala Val Gly Ala Val GlyAla Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Mix and Split All possible di peptides in three vessels Retain a sample from each vessel
  • 59.
  • 60.
    5. Identification ofstructures from mixed combinatorial synthesis Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Ala Val Gly Gly Gly Gly Ala Val Ala Ala Ala Gly Ala Val Val Val Val Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Val Val Val Val Val Val Val Val Mixture Inactive Mixture Inactive Mixture Active • 9 Possible tripeptides in active mixture • All end in valine • Add valine to the three retained dipeptide mixtures 5.1 Recursive Deconvolution
  • 61.
    Gly Ala Val Gly Ala Val Gly Ala Val Gly Gly Gly Ala Ala Ala Val Val Val Val Val Val Gly Ala Val Gly Ala Val Gly Ala Val Gly Gly Gly Ala Ala Ala Val Val Val Val Val Val Val Val Val Val Val Val Active •Active component narrowed down to one of three possible tripeptides • Synthesise each tripeptide and test 5. Identification of structures from mixed combinatorial synthesis 5.1 Recursive Deconvolution
  • 62.
    NH O NH2 HN O O HN MeOS SOMe O H2N H N H H Lysine Tryptophan NH2 NH2 5.2 Tagging: SCAL= Safety CAtch Linker 5. Identification of structures from mixed combinatorial synthesis
  • 63.
    NH2 NH2 RCHBrCO2H Step 1 NH2 NH O R Br amino acid(aa1) Tag 1 HN NH O R Br aa1 NH2 R'NH2 Step 2 HN NH O R NHR' aa1 NH2 amino acid(aa 2) Tag 2 HN NH O R NHR' aa1 aa2 NH2 R"COCl Step 3 HN NH O R NR'COR" aa1 aa2 NH2 amino acid(aa 3) Tag 3 HN NH O R NR'COR" aa1 aa2 aa3 NH2 5.2 Tagging Example
  • 64.
    N H XN H X N H X N H X N H X N H XN H XN H XN H XN H XN H X N H XN H XN H XN H XN H XN H X 6. Identification of structures from combinatorial synthesis 6.2 Photolithography - example N H XN H XN H XN H XN H XN H X M A S K 1 Mask LIGHT LIGHT N H XN H XN H XN H X N H XN H XN H XN H XN H XN H X N H X C O 2 H coupling N H X N H X N H X N H X N H X N H X N H XN H X N H X N H 2 N H 2 N H 2 N H XN H XN H XN H 2N H 2N H X N H XN H XN H XN H XN H XN H X Deprotection
  • 65.
    Y Y Y repeat 6.Identification of structures from combinatorial synthesis 6.2 Photolithography - example Y amino acids O M e O M eO O 2 N O X= Nitroveratryloxycarbonyl fluorescent tag Target receptor Y
  • 66.
    SEPARATIONAND ANALYSISOF COMBINATORIALLIBRARIES Separation and analysis of combinatorial libraries places a high demand on existing analytical techniques because The quantities to be analysed are very small The analysis should be non destructive and allow the recovery of the product The methods must be suitable for rapid parallel analysis
  • 67.
  • 68.
    Screening Screening is theprocess performed to identify the biologically active compound among all the compounds synthesised. The most commonly used screening methods in combinatorial chemistry are 1. Virtual screening 2. High throughput screening
  • 69.
    Virtual screening Virtual screeningrefers to the use of computers to predict whether a compound will show a desired activity or not on the basis of its two dimensional and three dimensional structure.
  • 70.
    High-throughput screening(HTS) HTS involvesthe process of finding an active compound against a chosen target using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-throughput screening allows a researcher to quickly conduct millions of chemical, genetic, or pharmacological tests. The results of these experiments provide starting points for drug design and for understanding the interaction or role of a particular biochemical process in biology.
  • 71.
    Assay plate preparation Reactionobservation Automation systems Hit selection Experimental design and data analysis Quality control Steps involved in HTS
  • 72.
  • 73.
    Conclusion The last tenyears has seen an explosion in the exploration and adoption of combinatorial techniques. Indeed, it is difficult to identify any other topic in chemistry that has ever caught the imagination of chemists with such fervour. Combinatorial chemistry as a technique for the rapid synthesis of drug-like compounds will continue to make a major impact on the way drug molecules are discovered. For pharmaceutical chemists at least the reason for this change is not hard to fathom. 20 years ago the market for pharmaceuticals was growing at around 10% per annum but more recently the rate of the market growth as decline. At the same time, cost constraints on pharmaceutical research have forced the investigation of methods that offer higher productivity at lower expenses. The belief that combinatorial chemistry will allow the productive and cost-efficient generation of both compounds and drug molecules has fuelled enormous investment in this area. Combinatorial chemistry as a technique for the rapid synthesis of drug-like compounds will continue to make a major impact on the way drug molecules are discovered.