| Budget Amount *help |
¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 1999: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1998: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Research Abstract |
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.
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