Natural amino acids targeting

This review describes designed and folded helical proteins, )5-sheet proteins, a )5)5a-motif and TASP proteins that are targets for functionalization. The functionalization of folded polypeptides using natural amino acids to form catalysts... 

In 1991, we first introduced the one-bead one-compound (OBOC ) combinatorial library method.1 Since then, it has been successfully applied to the identification of ligands for a large number of biological targets.2,3 Using well-established on-bead binding or functional assays, the OBOC method is highly efficient and practical. A random library of millions of beads can be rapidly screened in parallel for a specific acceptor molecule (receptor, antibody, enzyme, virus, etc.). The amount of acceptor needed is minute compared to solution phase assay in microtiter plates. The positive beads with active compounds are easily isolated and subjected to structural determination. For peptides that contain natural amino acids and have a free N-terminus, we routinely use an automatic protein sequencer with Edman chemistry, which converts each a-amino acid sequentially to its phenylthiohydantoin (PTH) derivatives, to determine the structure of peptide on the positive beads. 

Amino acids are the monomers from which nature produces proteins and enzymes. As such, they form an important part of the chiral pool. Histidine contains an imidazole ring in the sidechain and thus is a logical target for the synthesis of functionalised and chiral NHC, Given that a primary amine, as found in natural amino acids, is a prerequisite for standard imidazole ring forming reactions [60], it is surprising that only a few protocols are found in the literature where an amino acid [61-66] or its respective alcohol [64,67] forms part of a reaction that leads to a carbene precursor,... 

Cyclomarin A 98 exhibits cytotoxicity towards cancer cells and has antiinflammatory activity. It is a cyclopeptide isolated from an actinomycete and has attracted the attention of synthetic chemists due to the number of non-natural amino acids present in this structure. The (2S,4R)-D-hydroxyleucine 103 contained within the target has been prepared by using the Davis chiral auxiliary vide supra) Condensation of an enantiopure /7-toluenesulfinamide 100 with aldehyde 99 afforded sulfinimine 101. 

New Bioconjugation Methods Targeting the Natural Amino Acids... 

The hydrocarbon skeleton of the target is that of the amino acid phenylalanine. The configuration is (S), the same as the natural amino acid, so we can use the standard amino acid to hydroxy acid conversion via diazotization, described on p. 1105 of the textbook, which goes with retention of configuration. The aromatic ring needs hydrogenating too. 

The first synthesis of the natural amino acid L-ergothioneine (not depicted) was completed by Yadan and featured the direct conversion of an imidazole to an imidazole-2-thione. Treatment of 61 with phenyl chlorothiono-formate followed by base led to a ring-opening/ring-closing cascade that proceeded through intermediate 62. Compound 63 was elaborated to the target amino acid. 

The future of complex VNP development lies in the conjunction of molecular biology approaches and bioconjugation chemistry, particularly in terms of the ability to access both natural amino acids and uAAs side chains for modification in the same VNP. This will allow the incorporation of multiple moieties such as targeting ligands, therapeutic and imaging molecules. 

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