COMBINATORIAL CHEMISTRY- AN OVERVIEW ( FOR MEDICAL & PHARMA STUDENTS )

COMBINATORIALCHEMISTRY

BY

AAROMAL SATHEESH

INTRODUCTION THE BASIC PRINCIPLE OF COMBINATORIAL CHEMISTRY IS TO PREPARE A LARGE NUMBER OF

SIMILAR COMPOUNDS AT THE SAME TIME INSTEAD OF SYNTHESIZING COMPOUNDS IN A

CONVENTIONAL ONE AT- A-TIME MANNER.

THE CHARACTERISTIC OF COMBINATORIAL SYNTHESIS IS THAT DIFFERENT COMPOUNDS ARE

GENERATED SIMULTANEOUSLY UNDER IDENTICAL REACTION CONDITIONS IN A SYSTEMATIC

MANNER, SO THAT IDEALLY THE PRODUCTS OF ALL POSSIBLE COMBINATIONS OF A GIVEN SET OF

STARTING MATERIALS (TERMED BUILDING BLOCKS) WILL BE OBTAINED AT ONCE.

THE COLLECTION OF THESE FINALLY SYNTHESIZED COMPOUNDS IS REFERRED TO AS A

COMBINATORIAL LIBRARY.

COMBINATORIAL CHEMISTRY IS A NEW METHOD DEVELOPED BY ACADEMICS AND RESEARCHERS TO

REDUCE THE TIME AND COST OF PRODUCING EFFECTIVE, MARKETABLE AND COMPETITIVE NEW DRUGS.

• ÁRPÁD FURKA IS CONSIDERED TO BE ONE OF THE FATHERS OF COMBINATORIAL SYNTHESIS.HE

INTRODUCED THE COMMONLY USED SPLIT -AND- POOL METHODS IN 1982.

COMBINATORIAL LIBRARYDEF: COLLECTION OF FINALLY SYNTHESIZED COMPOUNDS

SIZE: DEPENDS ON THE NUMBER OF BUILDING BLOCKS USED PER REACTION ANDTHE NUMBER OF REACTION STEPS, IN WHICH A NEW BUILDING BLOCK IS INTRODUCED

TYPICAL: 102 UP TO 105 COMPOUNDS

APPLICATIONS Applications of combinatorial chemistry are very wide Scientists use

combinatorial chemistry to create large populations of molecules that can be screened efficiently.

By producing larger, more diverse compound libraries, companies increase the probability that they will find novel compounds of significant therapeutic and commercial value.

Provides a stimulus for robot-controlled and immobilization strategies that allow high-thrughput and multiple parallel approaches to drug discovery

• TECHNIQUES OF COMBINATORIAL CHEMISTRY• SOLID SUPPORT SYNTHESIS: (ON SOLID PHASE SUCH AS RESIN BEAD,

• PINS, OR CHIPS)

• SPLIT AND MIX METHOD

• PARALLEL SYNTHESIS

• SOLUTION PHASE SYNTHESIS (IN SOLVENT IN THE REACTION FLASK

SOLID PHASE SYNTHESISReactants are bound to a polymeric surface and modified whilst still attached. Final

product is released at the end of the synthesis

ADVANTAGES

•Specific reactants can be bound to specific beads

•Beads can be mixed and reacted in the same reaction vessel

•Products formed are distinctive for each bead and physically distinct

•Excess reagents can be used to drive reactions to completion

•Excess reagents and by products are easily removed

•Reaction intermediates are attached to bead and do not need to be isolated and purified

•Individual beads can be separated to isolate individual products

•Polymeric support can be regenerated and re-used after cleaving the product

•Automation is possible

REQUIREMENTS

• A RESIN BEAD OR A FUNCTIONALISED SURFACE TO ACT AS A SOLID SUPPORT

• AN ANCHOR OR LINKER

• A BOND LINKING THE SUBSTRATE TO THE LINKER. THE BOND MUST BE STABLE TO THE REACTION CONDITIONS USED IN THE SYNTHESIS

• A MEANS OF CLEAVING THE PRODUCT FROM THE LINKER AT THE END

• PROTECTING GROUPS FOR FUNCTIONAL GROUPS NOT INVOLVED IN THE SYNTHESIS

• )

• SUPPORTS AND LINKERS• MOST SOLID STATE COMBINATORIAL CHEMISTRY IS CONDUCTED BY USING POLYMER BEADS OF 10 TO

• 750 ΜM IN DIAMETER.

• THESE SWELL IN ORGANIC SOLVENTS ALLOWING FREE DIFFUSION OF SOLVENT AND REAGENT INTO

THE INTERIOR OF THE BEAD.

• THE POLYMERS ARE INERT EXCEPT FOR THE FUNCTIONAL GROUPS TO WHICH THE MOLECULES

• ARE ATTACHED

• POLYSTYRENE RESIN: POLYSTYRENE WITH DI-VINYL BENZENE CROSS LINKED

• TENTA-GEL RESIN: POLYSTYRENE WITH PEG CROSS LINKED

• POLY ACRYLAMIDE RESINS: AMIDE CONTAINING RESIN

• CERAMIC/ GLASS BEADS: USED FOR HIGH TEMP AND PRESSURE REACTIONS.

• LINKERS ARE USUALLY ATTACHED BECAUSE

• THIS HELPS IN DETACHMENT OF THE RESIN WITHOUT DESTROYING THE MOLECULE.

• IT ALLOWS GREATER FREEDOM OF ROTATION TO THE MOLECULES ATTACHED.

• Beads must be able to swell in the solvent used, and remain

stable

• Most reactions occur in the bead interior

Swelling

Linkers

Resins are named to design the linkers..Ex:-

EQUIPMENTS USED IN SOLID PHASE

MIX AND SPLIT METHOD

•To use a standard synthetic route to produce a large variety of different analogues

where each reaction vessel or tube contains a mixture of products

•The identities of the structures in each vessel are not known with certainty

•Useful for finding a lead compound

•Capable of synthesising large numbers of compounds quickly

•Each mixture is tested for activity as the mixture

•Inactive mixtures are stored in combinatorial libraries

•Active mixtures are studied further to identify active component

WE WILL GOT 27 TRIPEPTIDES FROM 3 VIALS , EACH TRIPEPTIDES ARE

SYNTHESIZED AND FINALLY WE WILL GET ABOUT 34 MILLION PRODUCTS

(1,889,568 HEXAPEPTIDES / VIAL )

SOLUTION PHASE SYNTHESIS

PARALLEL PHASE SYNTHESIS

• To use a standard synthetic route to produce a range of analogues, with a

different analogue in each reaction vessel, tube or well

• The identity of each structure is known

• Useful for producing a range of analogues or drug optimisation

A) Houghton’s Tea Bag Procedure

• EACH TEA BAG CONTAINS BEADS AND IS LABELLED

• SEPARATE REACTIONS ARE CARRIED OUT ON EACH TEA BAG

• COMBINE TEA BAGS FOR COMMON REACTIONS OR WORK UP PROCEDURES

• A SINGLE PRODUCT IS SYNTHESISED WITHIN EACH TEABAG

• DIFFERENT PRODUCTS ARE FORMED IN DIFFERENT TEABAGS

• ECONOMY OF EFFORT - E.G. COMBINING TEA BAGS FOR WORKUPS

• CHEAP AND POSSIBLE FOR ANY LAB

• MANUAL PROCEDURE AND IS NOT SUITABLE FOR PRODUCING LARGE

QUANTITIES OF DIFFERENT PRODUCTS

B) Automated parallel synthesis

•Automated synthesisers are available with 42, 96 or 144 reaction vessels or wells

•Use beads or pins for solid phase support

•Reactions and work ups are carried out automatically

•Same synthetic route used for each vessel, but different reagents

•Different product obtained per vessel

ADVANTAGESFAST

Combinatorial approach can give rise to million of compound in same time as it will take to produce one compound by traditional method of synthesis .

ECONOMICAL

A negative result of mixture saves the effort of synthesis, purification & identification of each compound

EASY

Isolation purification & identification of active molecule from combinatorial library is relatively easy.

DRUG DISCOVERY

Mixed Combinatorial synthesis produces chemical pool. Probability of finding a molecule in a random screening process is proportional to the number of molecules subjected to the screening process

DRUG OPTIMIZATION

Parallel synthesis produces analogues with slight differences which is required for lead optimization

DISADVANTAGES

• Efficiency is highly affected by compound's size, solubility and function group.

• Compounds produced tend to be Achiral of Racemic

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