Guide Combinatorial Chemistry

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The preparation of building blocks requires a different skill set to combinatorial synthetic chemistry particularly large-scale chemistry, process research experience and an appreciation of experimental reaction design. Such dual skill sets are rarely found within the service industry. We are fortunate enough to have a dedicated team of some 10 scientists who prepare several hundreds of building blocks for our production teams to incorporate in their libraries.

We have found that access to these materials has several advantages. They allow the incorporation of certain sub-structures into libraries that are inaccessible using parallel synthesis limitations. Proprietary building blocks afford structurally novel compounds for screening and potentially an improved intellectual property position and help avoid me-too type compounds that are more universally available.

Such libraries have real added value to both client and service provider alike. The first commercially available compound libraries were subjected to relatively scant analytical interrogation. The past five years have seen this picture change from being an optional extra to becoming an integral part of determining a library compounds synthesis and properties.

In the mid s, analytical methods had improved such that the majority of compounds were analysed by MS and, separately, liquid chromatography LC. Analysis of library compounds became easier as the cost of MS interments was reduced and reliability and ease of operation improved. Other advances in technology introduced alternative LC detectors. Evaporative light scattering detectors have become commonplace in the industry and these mass-based detectors are capable of quantifying components using properties other than UV absorption the most widely accepted technique. However, these advances did not solve the key problem of determining the absolute purity of a new library compound without a standard, pure material.

One of the problems of such an analytical approach was that, occasionally, the MS signal and LC trace did not match and compound structure and or purity was mis-assigned. To cope with such numbers of new compounds requiring analysis more rapid analytical techniques particularly in LC became essential. Use of ballistic gradients became standard and run times per compound were reduced to two minutes or less. The trend of using stand-alone LC and loop injection MS in mode became the standard, most cost-effective method of analysing large lead discovery libraries.


The most recent development is the use of coupled LC-MS whereby each compound peak is analysed in the sample and compound purity and structure can be unambiguously assigned. This technique typically suffers from a low throughput, but a very recent development is the use of parallel injection ports from up to eight LC machines into a single mass spectrometer. This most recent technology has finally solved the seemingly impossible problem of analysing, in a truly qualitative way, large numbers of compound in synchrony with their synthesis. A traditional chemist can synthesize compounds per year.

A combinatorial robotic system can produce in a year thousands or millions compounds which can be tested for potential drug candidates in a high-throughput screening process.

Over the last few years, the combinatorial chemistry has emerged as an exciting new paradigm for the drug discovery. In a very short time the topic has become the focus of considerable scientific interest and research efforts Combinatorial synthesis on Solid-phase: Since Merrifield pioneered solid phase synthesis back in , work, which earns him a Nobel Prize, the subject, has changed radically. Many laboratories and companies focused on the development of technologies and chemistry suitable to SPS. This resulted in the spectacular outburst of combinatorial chemistry, which profoundly changed the approach for new drugs, new catalyst or new natural discovery.

Merrifield developed a series of chemical reactions that can be used to synthesise proteins. The direction of synthesis is opposite to that used in the cell. The intended carboxy terminal amino acid is anchored to a solid support. Then, the next amino acid is coupled to the first one.

In order to prevent further chain growth at this point, the amino acid, which is added, has its amino group blocked. After the coupling step, the block is removed from the primary amino group and the coupling reaction is repeated with the next amino acid The process continues until the peptide or protein is completed. Then, the molecule is cleaved from the solid support and any groups protecting amino acid side chains are removed.

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Finally, the peptide or protein is purified to remove partial products and products containing errors 6. Synthesis of Combinatorial Library: Combinatorial synthesis on solid phase can generate very large numbers of products, using a method described as mix and split synthesis.

This technique was pioneered by Furka and has been enthusiastically exploited by many others since its first disclosure. For example, Houghten has used mix and split on a macro scale in a "tea bag" approach for the generation of large libraries of peptides. The method works as follows: a sample of resin support material is divided into a number of equal portions x and each of these is individually reacted with a single different reagent. After completion of the reactions, and subsequent washing to remove excess reagents, the individual portions are recombined; the whole is thoroughly mixed, and may then be divided again into portions.

Reaction with a further set of activated reagents gives the complete set of possible dimeric: units as mixtures and this whole process may then be repeated as necessary for a total of n times.

Combinatorial chemistry and analog generation

The number of compounds obtained arises from the geometric increase in potential products; in this case x to the power of n. A simple example of a 3 x 3 x 3 library gives all 27 possible combinations of trimeric products. X, Y and Z could be amino acids, in which case the final products would be tripeptides, but more generally they could be any type of monomeric unit or chemical precursor. It can be seen that the mix and split procedure finally gives three mixtures each consisting of nine compounds each, and there are several ways of progressing these compounds to biological screening.

Although the compounds can be tested whilst still attached to the bead, a favored method is to test the compounds as a mixture following cleavage from the solid phase. Activity in any given mixture reveals the partial structure of active compounds within the library, as the residue coupled last usually the N-terminal residue is unique to each mixture. Identification of the most active compound relies on deconvoluting the active mixtures in the library through further synthesis and screening. In the example where the active structure is YXY, the mixture with Y at the terminal position will appear as the most active.

Having retained samples of the intermediate dimers on resin so-called "recursive" deconvolution addition of Y to each of the three mixtures will give all nine compounds with Y at the terminal position, and the second position defined by the mixture. The most active mixture here defines the middle position of the most active trimer to be residue X. Finally, the three individual compounds can be independently resynthesized and tested to reveal both the most potent compound and also some structure activity relationship data. In contrast, Lam et al.

Nineteen amino, acids were incorporated into pentapeptides to generate a library of almost two and a half million compounds. Bead picking using micromanipulation isolated the beads, and the active peptide structures were determined by microsequencing A modification of this method has allowed screening of such libraries in solution.

Structural Biochemistry/Bioinformatics/Combinatorial Chemistry

Linkers have been devised that allow several copies of the library compounds to be released sequentially. Using this method it is possible to identify an active mixture using a solution assay, and then return to the beads that produced these compounds, and redistribute them into smaller mixtures for retest. By repeatedly reducing the mixture size, ultimately to single compounds, the bead containing the most potent sequence may be identified and the peptide product sequenced 7.

Combinatorial synthesis in Solution: Despite the focus on the use of solid-phase techniques for the synthesis of combinatorial libraries, there have been few examples where libraries have successfully been made and screened in solution. The benefit of preparing libraries on resin beads has been explained as offering advantages in handling, especially where a need to separate excess reagents from the reaction products is attached to the resin. In most of case a simple filtration effects a rapid purification and the product are ready to further synthetic transformation.

But it should be remember that using solid phase chemistry brings several disadvantages as well.

Clearly the range of chemistry available on solid phase is limited and it is difficult to monitor the progress of reaction when the substrate and product are attached to the solid phase Indeed some groups have expressed a preference for solution libraries because there is no prior requirement to develop workable solid phase coupling and linking techniques.

The difficulty is purifying large number of compounds without sophisticated automated processes 8. Parallel Solution Phase synthesis: Manual or automated approaches can be used for the parallel preparation of tens to hundreds of analogues of a biologically active substrate. The products are synthesised using reliable coupling and functional group interconversion chemistry and are progressed to screening after removal of solvent and volatile by-products. Parallel and orthodox synthesis is compared below;. Orthodox synthesis usually involves a multistep sequence, e.

The next analogue is then designed, guided by the biological activity of the previous compound, prepared, and then screened. This process is repeated to optimise both activity and selectivity The library is screened, usually without purification, and with only minimal characterization of the individual compounds, using a rapid throughput screening technique 9. Panlabs have recently disclosed an interest in making large number of compounds as individual components using parallel, reliable solution chemistry.

Reactions are pushed to completion by the use of excess quantities of the reactive reagent, and are isolated by solvent - solvent extraction. There is no further purification, and thus they prefer to describe these samples as "reaction products". Resins for Solid Phase synthesis: In solid phase support synthesis, the solid support is generally based on a polystyrene resin. Each of these materials has advantages and disadvantages depending on the particular application.

In solvents, which swell the polymer well, the gel network consists of mostly solvent with only a small fraction of the total mass being polymer backbone. This allows relatively rapid diffusional access of reagents to reactive sites within the swollen bead.

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In solvents, which do not swell the polymer, the cross-linked network does not expand and the diffusion of reagents into the interior of the bead is impeded Sheppard also proposed the use of a new protection and linking strategy. The Merrifield approach depended on a benzyl ester linkage and Boc protection. But a more mild protection or deprotection were sought. The protecting group finally chosen was the fluorenylmethoxycarbonyl Fmoc which can be removed by base usually piperidine. Combinatorial Libraries: Two groups have recently disclosed solution libraries prepared in mixtures.

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In each case the groups from Glaxo and Pirrung have synthesised dimeric compounds using amide, ester or carbamate bond-forming reactions. Every library compound was prepared twice in mixtures of different composition. Testing all of these mixtures allows identification of likely active compounds without the need to resynthesise every compound in an active mixture.

In the glaxo example, 40 acid chlorides were reacted with 40 amines or alcohols to gives amides or ester respectively in two sets. In the first set, each acid chloride A was reacted with a stoichiometric amount of an equimolar mixture of all 40 nucleophiles N In the second set each amine or alcohol N was reacted with an equimolar mixture of the acid chlorides A The 80 mixtures of 40 components each were screened against a wide variety of pharmacological targets, and a positive result from any sample identified half of the structure of a likely active dimeric compound.