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

涉及非键硫-杂原子相互作用的新型功能分子的合成和表征

• 批准号: 10470470
• 负责人: NAGAO Yoshimitsu
• 金额: $ 5.76万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470470/
• 关键词: cysteine protease; cathepsin; μ-calpain; enzyme inhibition; reaction cascade; pyrrolinone; epoxysuccinic acid; peptidyl aldehyde; 酵素阻害; カルパイン; アミノ酸; 酵素加水分解; 不斉アルキル化反応; 不斉アルドール反応; アミノマロン酸

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.

组织蛋白酶B、H、L、S和K是属于木瓜蛋白酶超家族的哺乳动物溶酶体半胱氨酸蛋白酶。这些组织蛋白酶很可能在特定酶和激素的量的调节中起重要作用。钙蛋白酶（μ型和m型）是半胱氨酸蛋白酶家族的一种，广泛存在于细胞质中，可被钙离子激活。以α-羟基-α-（β-丙炔酰胺）丙二酸二乙酯为原料，通过碱性水解反应，成功地合成了手性5-取代3-吡咯啉-2-酮衍生物L-Ile-L-Pro-OH或L-Phe-NHCH取代基D22取代基D2 Ph。在所合成的手性吡咯啉酮类化合物中，含有L-Ile-L-Pro-OH的5S-乙氧羰基，5S-羟基-3-吡咯啉-2-酮被证明是最有效的组织蛋白酶B抑制剂。合成了一系列新的含不同氨基酸和N-取代哌嗪的手性环氧琥珀酸衍生物。筛选出1 - [（2S，3S）-环氧琥珀酰-L-亮氨酰]-4-（2-氯苯基）哌嗪对组织蛋白酶B和μ-钙蛋白酶具有选择性抑制活性。新的含对苯甲酰基的肽基化合物对组织蛋白酶B、H、L、S、K和μ-钙蛋白酶均有较强的抑制活性。其中，N-（N-对苯基苯甲酰基-L-缬氨酰基-L-环己基丙氨酸醛）对组织蛋白酶K的抑制活性具有一定的选择性。

项目成果

長尾善光: "廣川有機薬科学実験講座第2巻:創薬化学の基礎となる不斉反応" 廣川書店, 108 (1998)

长尾义光：《广川有机药物科学实验教程第2卷：作为药物化学基础的不对称反应》广川书店，108（1998）

Shigeki Sano: "Diastereoselective Alkylation of a Newly Designed Bislactim Ether toward the Asymmetric Synthesis of α-Alkylated Serines" Tetrahedron:Asymmetry. 9・20. 3611-3614 (1998)

Shigeki Sano：“新设计的双乳酰亚胺醚的非对映选择性烷基化，用于α-烷基化丝氨酸的不对称合成”四面体：不对称性9·20（1998）。

Jun Inoue: "Syntheses and SH-Enzyme Inhibitory Activities of New Epoxysuccinic Acid-Piperazine Derivatives against μ-Calpain and Cathepsin B"Drug Design and Discovery. 16・. 165-169 (1999)

Jun Inoue：“新型环氧琥珀酸哌嗪衍生物对μ-钙蛋白酶和组织蛋白酶 B 的合成和 SH 酶抑制活性”药物设计和发现 165-169。

Jun Inoue: "Syntheses and SH-Enzyme Inhibitory Activities of New Epoxysuccinic Acid-Piperazine Derivatives against μ-Calpain and Cathepsin B"Drug Design and Discovery. 16. 165-169 (1999)

Jun Inoue：“新型环氧琥珀酸哌嗪衍生物对 μ-钙蛋白酶和组织蛋白酶 B 的合成和 SH 酶抑制活性”药物设计和发现。16. 165-169 (1999)

Jun Inoue: "Syntheses and SH-Enzyme Inhibitory Activities of New Epoxysuccinic Acid-Piperazine Derivatives against μ-Calpain and Cathepsin B" Drug Design and Discovery. 16(in press). (1999)

Jun Inoue：“新型环氧琥珀酸哌嗪衍生物对 μ-钙蛋白酶和组织蛋白酶 B 的合成和 SH 酶抑制活性”药物设计和发现 16（出版中）。