Comb Chem Flashcards
How many organic molecules MW <850 are there?
How many have drug like properties?
From commercially avail catalogues how many combos?
10^200
10^4
6000000
Ridiculously big
Steps of drug disco
Choose target Biology validation Lead discovery SAR/refinement Lead optimisation
Comb chem
Technique for producing large no of compounds in less time
Using defend reaction routes, large variety of starting materials and reagents
Comb synthesis
All possible compounds from a range of stating materials generated together - library
3 requirements for comb chem
Highly efficient chemistry
Limited work up, isolation and purification
Rapid through put……. Automation
Three main comb strategies
Mixed (spilt and pool)
Parallel
Miniaturisation (eg spot synthesis)
Advantages of comb synth 4
Increase productivity
Prevent chemistry bottle necks
Companies can patent sooner
Cost saving and increased time for revenue generation
Comb chem was inspired by
SPPS
Solid phase peptide synthesis
SPPS
Peptide synthesis in solution
At each step it is isolated, purified and characterised
(A very long process if many amino acids)
Merrifield process
Attach starting material (First amino acid) to solid support ( resin bead)
Advantages of the resin bead solid support? 2
After each reaction we just wash off by products no sxcess…. We don’t need to isolate and purify
Can be automated
How to ensure reaction goes to completion?
Use large excess of reactants.
At the end of reaction we just remove insoluble material
Parallel synthesis for four dipeoetides involves how many steps
8
4 individual coupling reactions +
4 cleaving the molecules from the polymers
Mix and spilt synthesis requires how many steps for 4 amino acids?
4
Mix the polymers together so you have 2 mixtures.
React one mixture with one amino acid (2)
Remove polymers from both mixtures (2)
2+2=4
Mix and split results in
Sub mixtures
When calculating the number of steps remember
In practice you always need more, this is a minimum
Pro and con of mix and split?
Pro: fewer step so more practical for larger libraries
Con: you end up with a mixture
Ways around the issue of it being a mixture?
Test it while it’s still attached to the bead? (Fewer steps)
Test it while in a mixture, maybe only one has activity, you can go back and loot at it by conventional methods
Tea bag method
Each batch leads to individual compound that is kept physically separate in porous bag ( parallel synthesis with the efficiency of mix and split)
Microkans and nanokans
Polyethylene tea bag fitted with rf tag for automated sorting
Advantage of tea bagging
Allows combining the tea bags for common steps
Linkers
- a unit attached to the solid support that contains a functional group which the starting material in the synthesis can react with (i.e. provides point of attachment for small molecules)
When selecting linker consider
functional group(s) present in the chosen starting materials, and the functional group required in the product (after cleavage from the solid phase)
Linkers … How to attach carboxylic acid, amine, alcohol
Ester
Displace a Cl in som strange three benzene ring ting
Ether
