Combinatorial Chemistry - Medicinal Chemistry III B. Pharma 6th Semester

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


       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


       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

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