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

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