SYNTHESIS AND ENZYMATIC-HYDROLYSIS OF ASPIRIN-BASIC AMINO-ACID ETHYL-ESTERS

Aspirin L-arginine ethyl ester (As-Arg-OEt) and aspirin p-guanidino-L-phenylalanine ethyl ester (As-GPA-OEt) were synthesized and the hydrolyses of these compounds in the presence of trypsin (Tp) and carboxypeptidase B (CPB) were examined in order to evaluate their availability as prodrugs for aspirin. The ester bonds of both As-Arg-OEt and As-GPA-OEt were hydrolyzed by Tp at about one-tenth the rate of N-alpha-benzoyl-L-arginine ethyl ester, a specific substrate for Tp, which suggests that they are good substrates for this enzyme. Salicylic acid was generated in the hydrolysis of aspirin L-arginine (As-Arg-OH) by CPB after the hydrolysis of As-Arg-OH to salicyl L-arginine (Sa-Arg-OH). On the other hand, aspirin and salicyl p-guanidino-L-phenylalanines were not hydrolyzed by CPB, and the latter competitively inhibited the CPB-catalyzed hydrolysis of hippuryl-L-arginine. These results indicate that As-Arg-OEt and As-GPA-OEt were not utilized as prodrugs for aspirin. However, L-arginine, which has alkylguanidine in its side chain, was more available than p-guanidino-L-phenylalanine, which has phenylguanidine in its side chain, in the CPB-mediated release of drugs from their prodrugs.