Lecture 7 - Combinatorial Chemistry Flashcards
What is combinatorial chemistry and when is it used?
Simultaneous production of many compounds with defined structures in one reaction vessel, and then screening of the compounds in order to find one with the desired biological activity that can be used as a lead compound
What is parallel synthesis and when is it used?
Simultaneous production of many compounds, each within its own reaction vessel. Generally used for structure optimisation rather than finding a lead compound
What are the advantages of combinatorial chemistry over parallel synthesis?
Generates significantly more structures in a set period of time, therefore increases the chances of finding an active compound
Economically more efficient as no time is wasted carefully making each compound if none is a hit
What are the disadvantages of combinatorial chemistry over parallel synthesis?
If one of the compounds in the mixture is a hit, structural determination is very difficult. If there is a false positive, lots of effort can be spent looking for an active compound that is not there
There is always a possibility that not all expected structures are created
What is solid phase synthesis and when is it used?
A means of compound synthesis where the reactions are carried out using a starting material that is linked to a solid support
Used during combinatorial chemistry and parallel synthesis
What are the 5 requirements of solid phase synthesis?
An insoluble polymeric support, such as a resin bead
A linker group covalently attached to the bead, which contains a functional group to which substrates can be added
A bond linking the substrate to the linker, that is stable to the reaction conditions (i.e. won’t break as more substrates are added)
A method of cleaving the produce from the linker
A method for protecting functional groups that are not involved in the reaction
Name two linkers that can be used in solid phase synthesis to produce peptides
Wang-Resin Linker
Rink-Resin Linker
Describe the process of solid phase synthesis using the Wang-Resin linker
React the linker with an amino acid that has the amine group protected
The OH of the linker and COOH of the amino acid react to form an ester bond
Remove the protective group on the amine
Add amino acids onto the now exposed amine
When complete, treat with TFA to detach the polypeptide
Describe the process of solid phase synthesis using the Rink-Resin linker
React the linker with an amino acid
The NH on the linker and COOH on the amino acid react to form an amide bond
When complete, treat with TFA to detach the polypeptide
What are the advantages of solid phase synthesis?
- Excess reagents can be removed simply by washing with a solvent, as the final product is bound to a solid support
- Easy removal of excess reagents means large excesses can be used, which drives the reaction to completion
- Intermediates are bound to the bead so do not need to be purified
- The support can be reused, as long as the product is cleaved off correctly
- The process can be automated
- As each product is attached to a bead, they can all be mixed together and each product separated at the end. This would be a disaster if done with solution chemistry
- Can produce large quantities of compounds in a short period of time
- Structures can sometimes have their biological activity tested while still attached to the bead
What are the two methods for carrying out combinatorial chemistry?
Mix and Split method
Dynamic combinatorial chemistry
What are the 3 methods for finding an active compound in a mixture following mix and split synthesis?
- Micromanipulation - each bead separated and individually tested
- Recursive deconvolution - some beads removed and tested at each stage of synthesis
- Sequential release - the beads split up into smaller mixtures and each mixture tested (less beads to go through micromanipulation if one mixture gives a hit)
What are the possible methods of structure determination once you have found an active compound?
- NMR - although often not enough product is produced for this
- Infrared - useful as doesn’t require the product to be released from the bead
- Tagging method - each time a component is added to the growing a compound, a code is also attached to the linker on a different functional group. Acts like a barcode. Useful, but double the amount of chemistry involved
What is dynamic combinatorial synthesis?
Combinatorial chemistry where the compounds are screened for biological activity in situ as they are synthesised
How is dynamic combinatorial synthesis carried out?
Include the desired target in the reaction flask
Any active compounds bind to the target when formed
Reactions for generating compounds are reversible and compounds break down - unless they have bound to the target which removes them from the equilibrium
Freeze the equilibrium mixture to identify the active compounds
What is a disadvantage of solid phase synthesis?
When assaying for biological activity, the resin bead can interfere and lead to false positives or false negatives, so it is best to remove the product from the bead first
What is SPOS and when could it be used?
Solution phase organic synthesis
Can be used during parallel synthesis
What is a pro and a con of SPOS?
Fewer steps and materials needed than solid phase synthesis
Extraction techniques are needed to separate the aqueous phase from the organic phase, such as a lollipop phase separator
What are the two approaches to designing a lead compound?
Spider-like approach: A centroid or scaffold has many growing ‘arms’ of reactive functional groups
Fragment based lead discovery: Find epitopes (small molecules that bind to specific regions of the active site of the target) and link them together to form a compound
What are the advantages of using the spider-like approach to designing a lead compound?
Increases the chances of finding a compound that will interact with the target site
Good chance the drug will have good oral bioavailability
What are the challenges of using the spider-like approach to designing a lead compound?
Esters and other readily hydrolysed groups should be avoided
Need to avoid the functional groups gathering around one side of the scaffold (tadpole-like)
What are the challenges of using the fragment-based approach to designing a lead compound?
Can be difficult to identify how the fragment has bound to the target
Can be difficult to link the fragments to form a viable compound
What rules must each fragment in ‘fragment-based lead discovery’ obey if the resulting compound is to obey Lipinski’s rules?
- MW < 300
- Less than or equal to 3 H bond donors
- Less than or equal to 3 H bond accepters
- cLogP value less than or equal to 3
- Less than or equal to 3 rotatable bonds
- Polar surface area less than or equal to 60 angstroms squared
