Ian Eggleston - Combinatorial Chemistry Flashcards
Where can lead compounds come from? (6)
1) Natural products (aspirin, morphine, quinine…)
2) Synthetic compound collections
3) Existing drugs (penicillins)
4) Natural receptor ligands, enzyme substrates etc…
5) Rational (computer aided) design
6) COMBINATORIAL SYNTHESIS
What is Combinatorial Chemistry?
- Techniques for producing large numbers of compounds in a short period of time
- Uses defined reaction routes and large variety of starting materials and reagents
- Combinatorial synthesis = all possible compounds from a range of starting materials generated together to form a LIBRARY
Combinatorial synthesis can be done as mixtures in a single flask or in _____
Parallel (produces single products)
List 4 advantages of using combinatorial chemistry
1) Vast increases in productivity
2) Chemistry ‘bottlenecks’ in drug discover process can be prevented
3) Companies can patent sooner
4) Cost savings and increased time for revenue generation
Combinatorial chemistry was inspired by what?
What is this?
Solid Phase Peptide Synthesis
- Orthodox synthesis
- Each compound prepared one at a time
- Each individual compound isolated, purified and characterised
List some advantages in combinatorial synthesis
1) Starting materials (AA) and products attached to insoluble support (resin bead) so excess reagents and by products can be removed by filtering and washing the resin
2) Large excess of reagent can be used to drive reactions to completion
3) No need to isolate and purify intermediate compounds
4) Can be automated
How would 4 compounds be prepared from Ala and Gly using parallel synthesis?
- In separate vessels
- Couple…
A-p with A
A-p with G
G-p with A
G-p with G - The cleave the p (protecting group) for each
8 Reactions will take place
How would 4 compounds be prepared from Ala and Gly using Mix and Split synthesis?
- Two resins in two reaction vessels
- A-p and G-p
- Mix the resins
- A-p, G-p in same vessel
- Split into 2 vessels
- A-p, G-p x2
- Couple one with A and one with G
- A-A-p, A-G-p
- G-A-p, G-G-p
- Then cleave the p from each vessel
4 Reactions - Couple and Cleave x2
If Tripeptides were to be made from 3 amino acid building blocks Ala, Gly and Trp using Parallel synthesis, how many reactions will take place?
- Couple
- A to all three = 3 products
- G to all three = 3 products
- T to all three = 3 products
(9 reactions) - Couple each of the 3 products for each one to all three
- 9 products
- 9 products
- 9 products
(27 reactions) - Cleave each of the 9 products for each one
(27 reactions)
= 63 REACTIONS IN TOTAL
If Tripeptides were to be made from 3 amino acid building blocks Ala, Gly and Trp using Mix and Split Synthesis, how many reactions will take place?
- Add A,G,T to a vessel
- Mix
- Split into 3 vessels = A,G,T in each
- Couple A to one, G to one and T to one vessel
(3 reactions) - Left with 3 products in each (9 products)
- Mix the 3 vessels together
- Split back into 3
- 9 products in each vessel (27 products)
- Add A,G,T to each vessel to couple again
(3 reactions) - 9 products in each vessel (27 products)
- Cleave each vessel group from -p
(3 reactions)
= 9 REACTIONS IN TOTAL
What is the role of a ‘linker’?
- A unit attached to the solid support that contains a functional group which the starting material in the synthesis can react with
- Provides point of attachment for small molecules
e. g OH react with COOH
e. g Cl react with NH2
e. g O-= react with OH
What is an Fmoc group?
- A protecting group that is removed in order for reactions to take place
Explain Traceless linkers and ‘cyclo-release’
Traceless linkers - On cleavage of the product from the solid resin, the functional group is replaced with a hydrogen
Cyclo-Release - Functional group used to join one of the starting materials to the solid support/resin gets incorporated into the final product
What is the role of scavenger resins?
- Polymers with bound functional groups that react with specific by products/impurities/xs reagents made in a reaction
- e.g if A is in excess reacting with B
- A-B will form and there will be A left over
- the scavenger (x-resin) will react with xs A, leaving A-B
- The solution is filtered and evaporated removing A-B and the scavenger resin with xs A is left (A-x-resin)
Give an example of a scavenger resin and the excess reagent it removes…
- RNH2 and resin–N=C=O
- RHalide, RCHO and resin–SH
