Combinatorial Chemistry Flashcards
What is combinatorial chemistry?
It is the simultaneous reaction of a set of compounds with a second set of compounds to produce a set of products known as a combinatorial library
How many products would starting with 10 compounds and reacting these with 10 different building blocks at each stage of a 2 stage synthesis yield?
1000 compounds - in theory
What is solid phase synthesis?
Where the chemistry is done in the solid phase, usually taking the form of a resin bead that compounds bind to.
What’re the benefits of solid phase synthesis?
Reagents can be used in excess to drive reaction to completion - difficult in solution chemistry
Purification is easy - simply wash solid support
Is easily automated
What’re the disadvantages of solid phase synthesis?
Fewer solid supported reactions
Scaling up is expensive
Research is required to find suitable support and linker - can be slow
What’re the advantages of solution phase synthesis?
Limitless organic reactions
Scale up is easy & cheap
RDS is optimising the chemistry involved
What’re the disadvantages of solution phase synthesis?
Reagents cannot be used in excess - requires additional purification
Purification can be difficult
Automation is difficult
What is Merrifield’s peptide synthesis resin?
Partially cross-linked polystyrene beads that have a chloromethyl group attached - so that amino acid can bind
What end of the amino acid binds to the solid phase support in Merrifield’s synthesis? What is done to ensure this?
The C-terminal
BOC is used to protect the amine
AA is joined by SN2 reaction and BOC is then removed
Product is then purified by resin washing
What happens after an amino acid is successfully added to a resin bead in Merrifield’s synthesis?
A N-protected DCC activated carboxylic acid is added - an amide bond is formed
Protecting group is removed and product is purified by resin washing
The product is then cleaved from the resin bead.
What reagents are used to cleave the product from the resin bead inn Merrifield’s synthesis?
HBr/CF3COOH
CF3COOH = triflouroacetic acid
What’re the advantages of the Tentagel resin bead?
Bead can be functionalised with a range of different groups
Reacting groups are further from the surface of the bead - polyethylene glycol (PEG) insert separates them
What other resin is used in combinatorial chemistry? (Other than Merrifield’s and Tentagel beads)
The Wang resin
Where is parallel synthesis in solution carried out?
In a 96 well plate
What is Houghton’s Tea Bag procedure?
Each tea bag (resin in a propylene mesh) is added to a reaction vessel - polyethylene bottle
The first AA is then attached to the solid phase resin - alkylation reaction.
The second AA is then added, this is combined with the first AAs and is deprotected
What’re the steps taken for the Pin and Well Grid Array process?
Pins are dipped into solution with different compounds in each well
Wells are then heated, binding the compound in each well to its respective pin.
It is then resin washed and dipped into the next set of wells, containing a new set of different compounds.
The wells are then heated.
The cycle can be repeated until desired product is obtained. product is isolated by cleavage from resin
What is Furka’s Mix and Split technique?
Initial compounds are bound to resin beads (3)
COMBINE, MIX and SPLIT into 3 new portions, gives 9 new compounds
This is then combined, mixed and split into 3 new portions - yielding 27 new compounds
- every possible combination is made from the compounds used
What is ‘sequential release’?
Where 50% of a drug is removed using base first, with the other 50% being removed by acid
- 2 products on 1 bead
The beads are then split into small groups and tested for activity
Why is the ‘sequential release’ method attractive?
Because it allows fast identification of the active compound(s) in the mixture of products in a combinatorial library.
