CBZ-Amino Acids

Introduction

CBZ-amino acids are a type of amino acids protected by benzyloxycarbonyl (CBZ) amino protecting group. CBZ is an old amino protecting group discovered by Bergmann in 1932, but it is still used today. The advantages are that the preparation of reagents and the introduction of protective groups are relatively easy and N-benzyloxycarbonyl amino acids and peptides are easy to crystallize and are relatively stable. In addition, CBZ-amino acids are not easy to racemize when activated as well as they can be selectively removed by a variety of mild methods. For the introduction of benzyloxycarbonyl, CBZ-Cl is generally used. The free amino groups can be easily reacted with CBZ-Cl under alkaline conditions controlled by NaOH or NaHCO3 to obtain N-benzyloxycarbonyl-amino acids.

Preparation of CBZ-amino acids. Fig 1. Preparation of CBZ-amino acids.

Except that CBZ- Leucine is an oil substance, most CBZ-amino acids derivatives can be crystallized. Some N-benzyloxycarbonyl amino acids can form eutectic with its sodium salt in a certain proportion. Those eutectic products have higher melting point and are difficult to dissolve in organic solvents. For example, when phenylalanine is subjected to benzyloxycarbonylation and then acid is added to precipitate CBZ-Phenylalanine, a eutectic product (melting point of 144°C) is often obtained. The eutectic product can be completely converted into CBZ-Phenylalanine when dissolved with ethyl acetate and 1M HCl and dissolves in ethyl acetate. Therefore, with the exception of CBZ-Glycine, the pure CBZ-amino acids are generally obtained by acidification and extraction with organic solvents.

Applications

CBZ-amino acids have the abilities of cholecystokinin receptor antagonist. With the exception of CBZ-alanine, CBZ -glycine, and N-CBZ-lysine, all CBZ-amino acids derivatives are able to inhibit the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin. In general, the ability of CBZ-amino acids to inhibit the secretion of amylase has a good correlation with the ability of amino acid derivatives to inhibit the binding of 255I-cholecystokinin. The inhibition of cholecystokinin-stimulated amylase secretion is competitive, completely reversible, and specific for those secretagogues that interact with cholecystokinin receptors. Different CBZ-amino acids can inhibit cholecystokinin up to 100 times, of which CBZ-cystine has the strongest effect. This change in potency is mainly, but not exclusively, the role of the hydrophobicity of amino acid side chains.

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