Combinatorial Chemistry Flashcards
What are the steps involved in conventional organic synthesis?
one peptide reacts with BOC which attaches at the amino group
- protects the amino group by making it inactive and stopping the reaction from happening at that section
one peptide reacts with methanol (MeOH) to block its carboxylic acid group
= these reactions means there is only one possible product as each peptide has either its amino or carboxylic acid group blocked
both peptides are joined together by DCC which is a coupling reagent
- forms a dipeptide
BOC is removed by TFA
methyl is removed by base catalysed hydrolysis (NaOH)
What are TFA, BOC and DCC? What are their functions?
BOC
- tertiary butyl oxycarbonyl
= protects the amino group of the peptide
DCC
- dicyclohexylcarbodimide
= is the coupling reagent which joins the peptides
TFA
- trifluoroacetic acid
= removes BOC
What are the disadvantages of conventional organic synthesis?
process is time consuming
- each step can take a few days each
side reactions/incomplete reactions can lead to reduced yields
each intermediate must be identified and purity confirmed
- inefficient purification techniques can lead to reduced yields
What is the key difference between conventional organic synthesis and solid phase organic synthesis?
with solid phase organic synthesis, the reactants are tethered to a resin bead throughout the reaction
SPOS - is a type of combinatorial chemistry
What is the main advantage solid phase organic synthesis?
can be used to generate a wide range of different products quickly and efficiently
- has lead to the extensive use of combinatorial chemistry in drug development
What are the advantages of SPOS?
- impurities and unreacted reagents can be washed away
- process can be easily automated
- better yield
= no loss during intermediate purification
= no loss between transferring between vessels
= large excess of reagents can be used to drive reactions to completion
What are the disadvantages of SPOS?
- if reactions do not got to completion then mixtures will form
- insoluble by-products are not removed
- intermediates cannot be identified/identification happens at the end
= cannot assess product identity and extent of reaction of intermediates
How doe solid phase organic synthesis occur?
the oligo peptide (with BOC at the amino group) is linked to the resin bead
- via linker
TFA removes BOC
- to allow the next reaction
DCC joins the next peptide
TFA removes the second peptides BOC
- a third amino acid can be added or the peptide chain can be cleaved off the resin bead
How can the products from SPOS be identified? What are the two groups products can be divided into?
can be identified by
- NMR, IR and MS techniques
products can be divided into
- linear polymeric type compounds
- scaffold types with different molecular shapes
What is combinatorial chemistry?
use of SPOS techniques to produce different products using common reaction vessels
- prepares a large number of products in a single process
What is parallel synthesis?
combinatorial chemistry
- can be used to synthesise more than one compound at once
- resin is sealed in a bag with micrometer sized mesh
- the bag can be different in different amino acid solutions to bind different residues
- bags can be pooled for washing and deprotection reactions
- bags are split open and individual peptides can be cleaved
each bag can be number coded to see which amino acid solution it has reacted with
- microchip which record radio frequency is put in the bag and each reagent has its own frequency
What is the 96 well plate?
each well is 0.1 ml
- allows the use of multi-channel pipetting
two methods
1 - the resin is in the wells, reagents are added, the plate is agitated then the reagent is drained through valves in the bottom of the wells
2 - the resin is on the end of a pin and is dipped into reagents in the wells
What is the main disadvantage of combinatorial chemistry?
- only allows analysis of small amounts of sample
- are not being able to detect synergy
