Combinatorial chemistry amino acid synthesis

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

The discovery of this lead compound as a potent PDF inhibitor was a result of an integrated combinatorial and medicinal chemistry approach based on the proposed generic PDF inhibitor structure. This focused chemical library was designed by Chen et al. [79], and was prepared using solid-phase parallel synthesis in which 22 amines and 24 amino acids were used as building blocks, as outlined in Scheme 23. 

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

Bolton, G. L. Hodges, J. C. Rubin, J. R. Solid Phase Synthesis of Fused Bicyclic Amino Acid Derivatives via Intramolecular Pausin-Khand Cyclisation Versatile Scaffolds for Combinatorial Chemistry, Tetrahedron 1997,53, 6611-6634. 

Various N-alkylated derivatives of amino acids are natural products [e.g., H-D-(Me)Tyr-OH (D-surinamine) and H-(Me)Trp-OH (abrin) were found in cabbage tree bark1691] and many of them are used as enzyme inhibitors, receptor agonists and antagonists, building blocks for heterocyclic scaffolds in combinatorial chemistry, etc. In this section the preparation of N-alkyl amino acids in solution for their use in peptide synthesis is described. This implies that the synthetic procedures described in this section will ultimately result in V-alkyl amino acids appropriately protected for peptide synthesis. 

An asymmetric C-C coupling, one of the most important and challenging problems in synthetic organic chemistry, seems to be most appropriate for the creation of a complete set of diastereomers because of the applicability of a convergent, combinatorial strategy [38-40]. In Nature, such reactions are facilitated by lyases which catalyze the (usually reversible) addition of carbo-nucleophiles to C=0 double bonds, in a manner mechanistically most often categorized as aldol and Claisen additions or acyloin reactions [41], The most frequent reaction type is the aldol reaction, and some 30 lyases of the aldol type ( aldolases ) have been identified so far [42], of which the majority are involved in carbohydrate, amino acid, or hydroxy acid metabolism. This review will focus on the current state of development of this type of enzyme and will outline the scope and limitations for their preparative application in asymmetric synthesis. 

Several combinatorial approaches for the synthesis of glyco-amino acids have been developed, due to the complexity of carbohydrate conjugates. The synthetic challenge is to get access to these building blocks by automated synthesis in order to generate glycopeptides library, to fully understand their biological roles and to widen their use in medicinal chemistry. 

Combinatorial chemistry evolved from the field of solid state peptide synthesis in which peptides are prepared on a polymeric solid phase support. Such supports are traditionally composed of polymeric resin beads on to which the synthesis of a peptide is undertaken in a stepwise fashion with each amino acid being added sequentially to the peptide chain (Figure 15.1). In order to avoid the formation of side products each... 

In another approach, Hindsgaul et al. reported a combinatorial strategy to obtain glycohybrids (Scheme 5) [8]. Glycohybrids are derived from monosaccharides via a Michael reaction, followed by the derivatization of the carbonyl group with several amino acids. This chemistry was further extended to the solution phase parallel synthesis to obtain a library of several compounds. 

If a linear hexapeptide solution existed, it must have been present in Geysen s library (provided the synthesis worked perfectly, which is a separate issue). There are no additional umepresented sequences, and mathematically such libraries are called NP-complete (NP = non-deterministic polynomial time). Such NP-complete libraries are actually quite rare in combinatorial chemistry. Although there are infinite numbers of peptides, for Geysen s epitope mapping, he needed to examine only natural amino acids. This reduces the complexity for a sequence of length n to 20", a number that increases exponentially with n but nevertheless remains finite. 

Beginning in the late 1950s work in peptide synthesis was facilitated by the availabihty of protected amino acids, coupling agents, and pure solvents from commercial vendors. These chemical companies utilized chemistry mostly developed in academic laboratories. This synergism continues to the present and will be ongoing in the future as new peptide chemistry develops, especially for the building blocks necessary for combinatorial chenoistry. 

The principal difference between the synthesis of individual peptides and peptide libraries is that mixtures of amino acids, rather than individual amino acids, are incorporated into selected or all positions of the sequence of peptide libraries. However, all current peptide chemistry strategies can be used for the synthesis of peptide libraries. In general, library synthesis requires greater emphasis on simplicity and reproducibility of the synthesis process. Although soluble supports have also been used for peptide library synthesis,the majority of methods used to synthesize peptide combinatorial libraries utilize Merrifield s concept of solid-phase synthesis,which is based on the sequential assembly of peptides after covalent attachment of the C-terminal amino acid to a polymeric solid support. This enables the excess of reagents to be removed by simple wash and filtration processes, and avoids the... 

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