Combinatorial Methods

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  • Created by: LBCW0502
  • Created on: 09-10-19 11:28
What are the principles of combinatorial chemistry?
Generates a multitude of chemically related (congeneric) compounds so-called combinatorial libraries. Combinatorial chemistry in drug research gives access to a large number of compound libraries within a short period of time
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Why is combinatorial synthesis used?
Drug discovery and development is a long risky road (pre-discovery 3-6 years, clinical trials 6-7 years, getting drug to market 0.5-2 years). Combinatorial synthesis can be used find potential lead compounds
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Describe features of combinatorial diversity in nature
Screen large number of compounds (0.1% success rate) - not an effective method (issue with chemical diversity of compounds). Screen proteins, identify therapeutic indication. Organic molecules, nucleic acid base pairs
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State features of organic synthesis, combinatorial synthesis, multi-step combinatorial synthesis, multicomponent reaction (in terms of the number of products) - 1
Classical organic synthesis - 1 educt x 1 educt = 1 product. Combinatorial synthesis - 50 educts x 20 educts = 1000 products. Multi-step synthesis - 50 x 20 x 20 educts = 20,000 products (educt already exists, product/what is made)
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State features of organic synthesis, combinatorial synthesis, multi-step combinatorial synthesis, multicomponent reaction (in terms of the number of products) - 2
Multicomponent reaction (Ugi) - 50 x 20 x 5 x 200 educts = 1 million products
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How is a combinatorial library generated?
E.g. building blocks with 68 different residues in 10 positions generate a library of 20 million different compounds. Consideration of steric centres increases this number by a factor of four (80 million different compounds)
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What is SAR?
Structure - activity relationship. Tells you the key pharmacophore for activity (may obtain or lose activity)
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Describe features of solid phase techniques (1)
Used to carry out reactions where the starting material is linked to a solid support such as a resin bead. Several reactions can be carried out in sequences on attached molecule. Final structure is detached from solid support
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Describe features of solid phase techniques (2)
Bead, scaffold, immobilisation, three step synthesis, immobilisation product, cleavage, product
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What are the advantages of solid phase techniques? (1)
Excess reagents/unbound by products from each reaction can be easily removed by washing resin. Large excesses of reagents can be used to drive reactions to completion
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What are the advantages of solid phase techniques? (2)
Intermediates in a reaction sequence are bound to the bead (don't need to be purified). Polymeric support can be regenerated/re-used (if appropriate cleavage conditions/suitable anchor/linker groups are chosen), automation possible
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What are the advantages of solid phase techniques? (3)
Range of different starting materials can be bound to separate beads. Beads can be mixed together/separated to give individual products
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What are the essential requirements for solid phase synthesis? (1)
Cross-linked insoluble polymeric support which is inert to the synthetic conditions (resin bead). Anchor/linker covalently linked to the resin (anchor has a reactive functional group that can be used to attach a substrate)
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What are the essential requirements for solid phase synthesis? (2)
Bond linking substrate to the linker, which will be stable to the reaction conditions used in the synthesis. A means of cleaving the product or intermediates from the linker. Protecting groups for functional groups not involved in the synthetic route
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Give an example of a solid phase synthesis (1)
Merrifield resin peptide synthesis. Involves polystyrene beads where styrene is partially cross-linked with 1% divinylbenze. Beads derivatized with a chloromethyl group (anchor/linker) to which amino acids are coupled via an ester group
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Give an example of a solid phase synthesis (2)
Cleavage using acidic conditions (hydrofluoric acid)
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What is the disadvantage of using the polystyrene beads?
They are hydrophobic and the growing peptide chain is hydrophilic (not solvated, folds in on itself to form internal H bonds), hinders access of further amino acids to the exposed end of the growing chain
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Describe the combination of scaffolds and building blocks
E.g. 3 building blocks A1-A3 and 3 building blocks B1-B3. Yield 9 products A1B1-A3B3. In the same manner, 10 x 10 x 10 building blocks yield 1000 products A1B1C1 - A10B10C10
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What is the split and combine method for library synthesis? (1)
E.g. 25 possible dipeptides, carry out 25 separate experiments. Split/combine method, beads split between 5 reaction vials. first amino acid attached to beads using a different amino acid for each vial
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What is the split and combine method for library synthesis? (2)
Beads from all 5 flasks are collected, mixed together then split back into the 5 vials. Each vial now has the same mixture. Second amino acid is now coupled with a different amino acid being used for each vial
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What is the split and combine method for library synthesis? (3)
Each vial now contains 5 different peptides with no one vial containing the same dipeptide. Each mixture tested for activity (positive/active)
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What is the split and combine method for library synthesis? (4)
E.g. 3 mixtures with 9 different compounds in each reaction vessel
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What are the challenges in split synthesis?
Time consuming deconvolution process. Amount of material on one bead is insufficient for structural determination. Chemical history of compounds synthesised is lost. Difficult to identify the active compounds (partially solve by using encoding)
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What are the types of encoding strategies?
Positional encoding, graphical encoding, radiofrequency encoding, spectrometric encoding, chemical encoding
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What are the types of chemical encoding?
One bead to one compound approach, peptide nucleic acid encoding, DNA encoding
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What is one bead to one compound encoding?
Molecular structures synthesised on solid supports (beads). Each individual bead may contain a large number of such molecules, but all the molecules on that bead are identical
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Which reactions are involved in the synthesis of encoded cyclic peptoid libraries?
Deprotection and coupling
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What does DNA encoded libraries involve?
DNA sequences conjugated. Read specific coding sequence. (Synthesis of oligonucleotide-compound conjugates)
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What is PNA encoding? (1)
Attach peptide nucleic acid containing compounds to DNA microarray, wash. Read sequence the PNA containing molecule which is bound to DNA microarray. Determine sequence within compound in mixture. (Chemical structure of PNA and DNA oligomers, PNA)
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What is PNA encoding? (2)
PNA encoded split synthesis. Deconvolution by tagging with GC analysable molecules
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Give examples of lead compounds from combinatorial chemistry (1)
Bayer’s CB-1 antagonist. Ki of 4.6 nM – more active. Ki of 21 nM – less active
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Give examples of lead compounds from combinatorial chemistry (2)
Pfizer’s mGluR1 antagonist. Ki of 9 nM – more active. Ki of 14 nM – less active
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What are the major disadvantages of combinatorial synthesis?
Limited structural diversity of synthetic library. Wastage of much of raw material. Wastage of assay material. No de novo drug designed as yet based solely on combinatorial synthesis
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Card 2

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Why is combinatorial synthesis used?

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Drug discovery and development is a long risky road (pre-discovery 3-6 years, clinical trials 6-7 years, getting drug to market 0.5-2 years). Combinatorial synthesis can be used find potential lead compounds

Card 3

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Describe features of combinatorial diversity in nature

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Card 4

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State features of organic synthesis, combinatorial synthesis, multi-step combinatorial synthesis, multicomponent reaction (in terms of the number of products) - 1

Back

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Card 5

Front

State features of organic synthesis, combinatorial synthesis, multi-step combinatorial synthesis, multicomponent reaction (in terms of the number of products) - 2

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