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    Combinatorial and parallel synthesis are techniques used to generate compound libraries. Combinatorial synthesis produces mixtures of compounds within each reaction vessel, while parallel synthesis produces a single product in each vessel. Solid phase techniques are commonly used, as they allow for easy removal of excess reagents and automation. The key requirements for solid phase synthesis are a polymeric support, linker, means to attach substrates and cleave products, and protecting groups. Parallel synthesis is useful for focused optimization and can synthesize multiple pure molecules simultaneously using miniaturization and automated techniques. Combinatorial synthesis deliberately produces compound mixtures that are tested for activity without separation. The mix-and-split strategy maximizes structures obtained efficiently. Active compounds can be identified using tagging or photolithography techniques.

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    Combinatorial and parallel synthesis are techniques used to generate compound libraries. Combinatorial synthesis produces mixtures of compounds within each reaction vessel, while parallel synthesis produces a single product in each vessel. Solid phase techniques are commonly used, as they allow for easy removal of excess reagents and automation. The key requirements for solid phase synthesis are a polymeric support, linker, means to attach substrates and cleave products, and protecting groups. Parallel synthesis is useful for focused optimization and can synthesize multiple pure molecules simultaneously using miniaturization and automated techniques. Combinatorial synthesis deliberately produces compound mixtures that are tested for activity without separation. The mix-and-split strategy maximizes structures obtained efficiently. Active compounds can be identified using tagging or photolithography techniques.

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    91 views17 pages

    Combinatorial 2020

    Uploaded by

    esraa
    Combinatorial and parallel synthesis are techniques used to generate compound libraries. Combinatorial synthesis produces mixtures of compounds within each reaction vessel, while parallel synthesis produces a single product in each vessel. Solid phase techniques are commonly used, as they allow for easy removal of excess reagents and automation. The key requirements for solid phase synthesis are a polymeric support, linker, means to attach substrates and cleave products, and protecting groups. Parallel synthesis is useful for focused optimization and can synthesize multiple pure molecules simultaneously using miniaturization and automated techniques. Combinatorial synthesis deliberately produces compound mixtures that are tested for activity without separation. The mix-and-split strategy maximizes structures obtained efficiently. Active compounds can be identified using tagging or photolithography techniques.

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    of 17

    Combinatorial and

    parallel
    synthesis
    The full set of compounds produced by Combinatorial and
    parallel synthesis is called a compound library
    Combinatorial and parallel synthesis in medicinal
    chemistry projects

    Advantages of human genome project and the proteomic


    revolution that followed.
    The procedures used in combinatorial synthesis are designed to produce
    mixtures of different compounds within each reaction vessel, whereas
    those used in parallel synthesis produce a single product in each vessel.
    Solid phase techniques

    • Solid phase techniques can be used to carry out reactions


    where the starting material is linked to a solid support, such as
    a resin bead.
    • Advantages:
    • 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 (greater than 99%).
    • intermediates in a reaction sequence are bound to the bead
    and do not need to be purified.
    Advantages:

    • the polymeric support can be regenerated and reused.


    • automation is possible.
    • if a combinatorial synthesis is being carried out, a range
    of different starting materials can be bound to separate
    beads. The individual beads can be separated at the
    end of the experiment to give individual products.
    The 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
    Parallel
    synthesis

    • a reaction is carried out in a series of wells such that each well contains a
    single product. This method is a ‘quality rather than quantity’
    • often used for focused lead optimization studies.
    • typical medicinal chemist may synthesize one or two new entities a week.
    • With parallel synthesis, that same researcher can synthesize a dozen or
    more pure molecules.
    • can be carried out on solid phase and also be carried out in solution
    ''solution phase organic synthesis (SPOS)'‘
    • many techniques to facilitate SPOS. Eg. Amide synthesis.
    Eg. Amide synthesis

    Conventionally, a work-up procedure involves:


    1. Washing the organic solution with aqueous acid.
    2. Separate the two layers and organic layer is washed with an aqueous
    base.
    3. Separate the two layers , and then the organic layer is treated with a
    drying agent such as magnesium sulphate.
    4. The drying agent is filtered off and then the solvent is removed to afford
    the crude amide.
    5. Purification then has to be carried out by crystallization or
    chromatography.
    In parallel synthesis variety of useful techniques can also be
    used to minimize the work-up procedure:

    1. Equipment miniaturization: This enable one to perform up to 24


    reactions followed by 24 simultaneous evaporations on a normal heater
    stirrer unit.
    2. Multiple parallel or sequential automated chromatography units
    3. Microwave reactors can dramatically speed up reaction times.
    Combinatorial synthesis
    • In combinatorial synthesis, mixtures of compounds are
    deliberately produced in each reaction vessel,
    • The structures in each reaction vessel of a combinatorial
    synthesis are not separated and purified, but are tested for
    biological activity as a whole.
    • Active mix …..one or more cpd active or false positive.
    • Inactive mix …. then there is no need to continue studies on
    that mixture and it is stored.
    • Overall, there is an economy of effort, as a negative result for
    a mixture of 100 compounds saves the effort of synthesizing,
    purifying, and identifying each component of that mixture.
    The mix and split method in
    combinatorial synthesis
    • Mix and split strategy used to minimize the effort involved and
    to maximize the number of different structures obtained.
    • NO. OF POSSIBLE DIPEPTIDES.
    By using mix and split method:
    Each individual bead may contain a large number of molecules, but all
    the molecules on that bead are identical
    Structure determination of the active compound(s)
    1. Tagging:
    two molecules are built up on the same bead. One of these is the intended structure, the
    other is a molecular tag (usually a peptide or oligonucleotide) which will act as a code for
    each step of the synthesis.

    Compounds used for tagging must satisfy a number of criteria:


    (1) The concentration of the tag should be just sufficient for its analysis, that is, the majority of
    the linkers should be occupied by the combinatorial synthesis.
    (2) The tagging reaction must take place under conditions that are compatible with those used for
    the synthesis of the library compound.
    (3) It must be possible to separate the tag from the library compound.
    (4) Analysis of the tag should be rapid and accurate using methods that could be automated.
    2. Photolithography

    • Photolithography is a technique that permits miniaturization and spatial


    resolution such that specific products are synthesized on a plate of
    immobilized solid support.
    • In the synthesis of peptides, the solid support surface contains an amino
    group protected by the photolabile protecting group. Then by using
    different mask to de-protect certain sites and build the desired peptide by
    adding protected amino acid, The process can be repeated on a different
    region using a different mask.
    • incubate the plate with a fluorescently tagged receptor. Only those
    regions of the plate which contain active compounds will bind to the
    receptor and fluoresce. The fluorescence intensity can be measured using
    fluorescence microscopy and is a measure of the affinity of the compound
    for the receptor.
    2. Photolithography
    Photolithography

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