Abcs

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Patrick An Introduction to Medicinal Chemistry
3/e Chapter 14 COMBINATORIAL CHEMISTRY Part 1
Sections 14.1 14.4
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Contents Part 1 Sections 14.1
14.4 1. Definition 2. Solid Phase
Techniques 2.1. Advantages 2.2. Requirements
2.3. Examples of Solid Supports (2
slides) 2.4. Anchor or linker
2.4.1. Merrifield resin for peptide synthesis
(chloromethyl group) 2.4.2. Wang resin (2
slides) 2.4.3. Rink resin (2
slides) 2.4.4. Dihydropyran resin (2
slides) 3. Parallel Synthesis 3.1. Houghtons
Tea Bag Procedure 3.2. Automated parallel
synthesis (2 slides) 3.3. Automated parallel
synthesis of all 27 tripeptides from 3 amino
acids (2 slides) 4. Mixed Combinatorial
Synthesis (21 slides) 41 slides
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• 1. DEFINITION
• The automated synthesis of a large number of
  compounds 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
• 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

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• 2. 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

• 2.1 Advantages
• 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

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2. SOLID PHASE TECHNIQUES 2.2 Requirements

• A resin bead or a functionalised surface to act
  as a solid support
• An anchor or linker
• A bond linking the substrate to the linker. The
  bond must be stable to the reaction conditions
  used in the synthesis
• A means of cleaving the product from the linker
  at the end
• Protecting groups for functional groups not
  involved in the synthesis

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2. SOLID PHASE TECHNIQUES 2.3 Examples of Solid
Supports

• Partially cross-linked polystyrene beads
  hydrophobic in nature
• causes problems in peptide synthesis due to
  peptide folding
• Sheppards polyamide resin - more polar
• Tentagel resin - similar environment to ether or
  THF
• Beads, pins and functionalised glass surfaces

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2. SOLID PHASE TECHNIQUES 2.3

• Beads must be able to swell in the solvent used,
  and remain
• stable
• Most reactions occur in the bead interior

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2. SOLID PHASE TECHNIQUES 2.4 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

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2.4.1 Merrifield resin for peptide synthesis
(chloromethyl group)
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2.4.2 Wang resin
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2.4.2 Wang resin
Carboxylic acid
Carboxylic acid
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2.4.3 Rink resin
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2.4.3 Rink resin
Carboxylic acid
Primary amide
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2.4.4 Dihydropyran resin
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2.4.4 Dihydropyran resin
Alcohol
Alcohol
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3. 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

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3. Parallel Synthesis 3.1 Houghtons 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

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3. Parallel Synthesis 3.2 Automated parallel
synthesis
AUTOMATED SYNTHETIC MACHINES
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3. Parallel Synthesis 3.2 Automated parallel
synthesis

• 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

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3. Parallel Synthesis 3.3 Automated parallel
synthesis of all 27 tripeptides from 3 amino
acids
ETC
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3. Parallel Synthesis 3.3 Automated parallel
synthesis of all 27 tripeptides from 3 amino acids
27 TRIPEPTIDES
27 VIALS
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4. 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

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4. Mixed Combinatorial Synthesis The Mix and
Split Method

• Example
• - Synthesis of all possible dipeptides using 5
  amino acids
• Standard methods would involve 25 separate
  syntheses

Combinatorial procedure involves five separate
syntheses using a mix and split strategy
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
Synthesis of all possible tripeptides using 3
amino acids
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
MIX
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
SPLIT
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
MIX
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
SPLIT
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
No. of Tripeptides
9
9
9
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
No. of Tripeptides
9
9
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27 Tripeptides 3 Vials
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
TEST MIXTURES FOR ACTIVITY
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
Synthesise each tripeptide and test
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4. Mixed Combinatorial Synthesis The Mix and
Split Method
HEXAPEPTIDES
20 AMINO ACIDS
etc.
34 MILLION PRODUCTS
(1,889,568 hexapeptides / vial)