Amino Acids and Peptides. XXXV. Facile Preparation of p-Nitroanilide Analogs by the Solid-Phase Method

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p-Nitroanilides of amino acids and peptides are widely used as the chromogenic substrates for the determination of the activity of proteolytic enzymes. However, the preparation of a p-nitroanilide is not easy, in part due to the low nucleophilicity of the amino group of p-nitroaniline. A facile preparation of p-nitroanilide analog by the solid-phase method was investigated. 5-Amino-2-nitrobenzoic acid (Anb^<5,2>) was used instead of p-nitroaniline (pNA) for preparation of p-nitroanilide analogs. Anb^<5,2> was introduced on a p-methylbenzhydrylamine resin without protection of the amino group of Anb^<5,2> by the 2-(H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) method in the presence of p-dimethylaminopyridine. The coupling reaction of a N^α-, N^G-protected arginine with a Anb^<5,2>-resin was difficult to achieve by common coupling methods (such as the carbodiimide and diphenylphosphoryl azide methods), but the phosphoryl chloride method was relatively successful. Synthetic benzoyl-Arg-Anb^<5,2>-NH_2 and benzoyl-Arg-pNA were hydrolyzed by trypsin and the both reaction mixtures exhibited same spectroscopic characteristics. H-D-Val-Leu-Arg-Anb^<5,2>-NH_2,an analog of human urine kallikrein substrate, was readily prepared by the solid-phase method. H-Arg-Anb^<5,2>-OH and H-D-Val-Leu-Arg-Anb^<5,2>-OH were also synthesized on a Wang resin by the solid-phase method. The aqueous solubility of these free-carboxyl materials was better than those of the corresponding amide analogs. 4-Amino-3-nitrobenzoic acid (Anb^<4,3>) was also introduced on the p-methybenzhydrylamine resin, but the resulting H-Anb^<4,3>-resin did not react with N^α-, N^G-protected arginine by any of the coupling methods.
公益社団法人日本薬学会の論文
2000-11-01

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