Combinatorial Chemistry
• Combinatorial
and parallel synthesis have become established tools in drug discovery and drug
development
• Use
of a defined reaction route to produce a large number of compounds in a short
period of time
• Full
set of compounds produced in this way is called a compound library
• Reactions
to be carried out in several reaction vessels at the same time and under
identical conditions, but using different reagents for each vessel
• Research
groups can rapidly synthesize and screen thousands of structures in order to
find new lead compounds
• Identify
structure–activity relationships, and find analogues with good activity and
minimal side effects
• Combinatorial
synthesis- designed to produce mixtures of different compounds within each
reaction vessel
• Parallel
synthesis- produce a single product in each vessel- favored, because easy to
identify the structures that are synthesized
• Works
on Solid Phase Synthesis
• To
carry out reactions where the starting material is linked to a solid support,
such as a resin bead
• Several
reactions can then be carried out in sequence on the attached molecule
• Final
structure is then detached from the solid support
Advantages
• Since
products are bound to a solid support, excess reagents or unbound by-products
from each reaction can be easily removed by washing the resin
• large
excesses of reagents can be used to drive the reactions to completion- as
excess can be removed easily
• Intermediates
in a reaction sequence are bound to the bead and do not need to be purified
• Polymeric
support can be regenerated and reused
• Automation
is possible
• Beads
can be mixed together such that all the starting materials are treated with
another reagent in a single experiment
• Mixing
all starting materials together in solution chemistry is a recipe for disaster,
with polymerizations and side reactions producing a tarry mess
• Individual
beads can be separated at the end of the experiment to give individual products
Essential requirements for solid phase synthesis
• a
cross-linked insoluble polymeric support which is inert to the synthetic
conditions (e.g. a resin bead);
• an
anchor or linker covalently linked to the resin—the anchor has a reactive
functional group that can be used to attach a substrate;
• a
bond linking the substrate to the linker, which will be stable to the reaction
conditions used in the synthesis;
• a
means of cleaving the product or the intermediates from the linker;
• protecting
groups for functional groups not involved in the synthetic route
Solid Support
• Merrifield resin peptide synthesis
• Resin
involved consisted of polystyrene beads where the styrene is partially
cross-linked with 1% divinylbenzene
• Beads
are derivatized with a chloromethyl group (the anchor/ linker) to which amino
acids can be coupled via an ester group
• Ester
group is stable to the reaction conditions used in peptide synthesis
• Can
be cleaved at the end of the synthesis using vigorous acidic conditions
(hydrofluoric acid)
• One
disadvantage of polystyrene beads- hydrophobic
• growing
peptide chain is hydrophilic
• peptide
chain is not solvated and oft en folds in on itself to form internal hydrogen
bonds
• It
hinders access of further amino acids to the exposed end of the growing chain
• More
polar solid phases were developed, such as Sheppard’s polyamide resin
• Tentagel
resin is 80% polyethylene glycol
grafted to cross-linked polystyrene
• Regardless
of the polymer that is used, the bead should be capable of swelling in solvent
while remaining stable
• Swelling
is important because most of the reactions involved in solid phase synthesis
take place in the interior of the bead rather than on the surface
• Each
bead is a polymer and swelling involves unfolding of the polymer chains such
that solvent and reagents can move between the chains into the heart of the
polymer
Anchor/Linker
• Molecular
unit covalently attached to the polymer chain making up the solid support
• It
contains a reactive functional group with which the starting material in the
proposed synthesis can react
• Resulting
link must be stable to the reaction conditions
• Easily
cleaved to release the final compound once the synthesis is complete
• Different
linkers are used depending on:
• the
functional group which will be present on the starting material;
• the
functional group which is desired on the final product once it is released
• Wang
resin has a linker which is suitable for the attachment and release of
carboxylic acids
• It
can be used in peptide synthesis by linking an N -protected amino acid
to the resin by means of an ester link
Peptide Synthesis
Mix and split method in combinatorial synthesis
Solution Phase Synthesis
• Reaction
is carried out in a series of wells such that each well contains a single
product
• Method
is a ‘quality rather than quantity’ approach and is oft en used for focused
lead optimization studies
• Necessary
to remove or simplify the bottlenecks associated with classical organic
synthesis
• Include
laborious work-ups, extractions, solvent evaporations, and purifications
• With
parallel synthesis, that same researcher can synthesize a dozen or more pure
molecules
• Increasing
the synthetic output and speeding up the lead optimization process
• Solution
phase organic synthesis ( SPOS )
• Considering
the synthesis of an amide, which typically involves the reaction of a
carboxylic acid with an amine in the presence of a coupling reagent such as
dicyclohexylcarbodiimide (DCC)
• Work-up
procedure involves washing the organic solution with aqueous acid in order to
remove unreacted amine
• Once
the aqueous and organic layers have been separated,
• Organic
layer is washed with an aqueous base in order to remove unreacted acid
• Organic
layer is treated with a drying agent such as magnesium sulphate
• Drying
agent is filtered off and then the solvent is removed to afford the crude amide
• Purification
then has to be carried out by crystallization or chromatography
• One
would have to repeat all of these steps and this would prove both time
consuming and equipment intensive
• Possible
to house a mini-parallel synthesis laboratory in a fume cupboard for each
chemist
Parallel synthesis
