Synthesis and Characterization of New Functional Molecules Involving the Nonbonded Sulfur-Heteroatom Interactions

Cathepsins B， H， L， S，K are mammalian lysomal cysteine proteases that belong to the papain superfamily. Thesecathepsins most probably play an important role in the regulation of the amount of specific enzymesand hormones. The calpain (μ- and m-type isoforms), which belong to The cysteine protease familyexist ubiquitously in the cytosol and activated by calcium ion. Chiral 5-substituted3-pyrrolin-2-ones bearing L-Ile-L-Pro-OH or L-Phe-NHCH D22 D2Ph were successfully synthesized byutilizing a characteristic reaction cascade based on kaline hydrolysis of the correspondingdiethyl α-hydroxy-α-(β-propiolamide)malonates. Among the synthesized chiral pyrrolinones，5 s-ethoxycarbonyl,5s -hydroxy-3-pyrrolin-2-one bearing L-Ile-L-Pro-OH proved to be the most potent inhibitor againstcathepsin B. New chiral epoxysuccinic acid derivatives bearing various amino acids and N-substitutedpiperazines were synthesized. After screening these compounds, 1 - [(2s，3s)-epoxysuccinyl-L-leucyl]-4-(2-chlorophenyl)piperazine exhibited selective inhibitory activityagainst cathepsin B in comparison with that against μ-calpain. New peptidyl aldehydic compoundshaving a -phenylbenzoyl group showed fairly strong inhibitory activities against all the cathepsinsB， H， L, S and K and μ-calpain. Among these screened compounds，N-（N-p- happylebonezl - l- valyl-L-cyclohexylalaninal exhibited a little selectivity of inhibitory）activity against cathepsin K。

Cathepsins B, H, L, S, and K are mammalian lysosomal cysteine proteases that belong to the papain superfamily. These cathepsins most probably play an important role in the regulation of the amount of specific enzymes and hormones. The calpain (μ- and m-type isoforms), which belong to the cysteine protease family, exist ubiquitously in the cytosol and are activated by calcium ion. Chiral 5-substituted 3-pyrrolin-2-ones bearing L-Ile-L-Pro-OH or L-Phe-NHCHィイD22ィエD2Ph were successfully synthesized by utilizing a characteristic reaction cascade based on alkaline hydrolysis of the corresponding diethyl α-hydroxy-α-(β-propiolamide)malonates. Among the synthesized chiral pyrrolinones, 5S-ethoxycarbonyl, 5S-hydroxy-3-pyrrolin-2-one bearing L-Ile-L-Pro-OH proved to be the most potent inhibitor against cathepsin B. New chiral epoxysuccinic acid derivatives bearing various amino acids and N-substituted piperazines were synthesized. After screening these compounds, 1 - [(2S , 3S )-epoxysuccinyl-L-leucyl]-4-(2-chlorophenyl)piperazine exhibited selective inhibitory activity against cathepsin B in comparison with that against μ-calpain. New peptidyl aldehydic compounds having a p-phenylbenzoyl group showed fairly strong inhibitory activities against all the cathepsins B, H, L, S and K and μ-calpain. Among these screened compounds, N-(N-p-phenylbenzoyl-L-valyl-L-cyclohexylalaninal exhibited a little selectivity of inhibitory activity against cathepsin K.