1999 Fiscal Year Final Research Report Summary
Synthesis and Characterization of New Functional Molecules Involving the Nonbonded Sulfur-Heteroatom Interactions
| Project/Area Number |
10470470
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Chemical pharmacy
|
|---|
| Research Institution | The University of Tokushima |
|---|
Principal Investigator |
NAGAO Yoshimitsu The University of Tokushima, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (40027074)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SANO Shigeki The University of Tokushima, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (20226038)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Keywords | cysteine protease / cathepsin / μ-calpain / enzyme inhibition / reaction cascade / pyrrolinone / epoxysuccinic acid / peptidyl aldehyde |
|---|
| 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.
|
