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Medicinal Chemistry-III

Combinatorial Chemistry
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
Combinatorial Chemistry
• 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
Combinatorial Chemistry
• 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
Combinatorial Chemistry
• 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
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)
Solid Support
• 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

• 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
Solid Support
• 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
• 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

• It can be used in peptide synthesis by linking an N -protected amino acid to the resin
by means of an ester link
Mix and split method in combinatorial 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

• 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

• Include laborious work-ups, extractions, solvent evaporations, and purifications

• With parallel synthesis, that same researcher can synthesize a dozen or more pure
Solution Phase Synthesis
• 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
Solution Phase Synthesis
• 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
Parallel synthesis