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

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。通过利用基于相应的α-羟基-α-(β-丙炔酰胺)丙二酸二乙酯的碱性水解的特征级联反应，成功合成了带有L-Ile-L-Pro-OH或L-Phe-NHCHD22Ph的3-吡咯啉-2-酮。在合成的手性吡咯啉酮中，带有L-Ile-L-Pro-OH的5S-乙氧基羰基、5S-羟基-3-吡咯啉-2-酮被证明是组织蛋白酶B最有效的抑制剂。合成了带有各种氨基酸和N-取代哌嗪的新型手性环氧琥珀酸衍生物。筛选这些化合物后，与μ-钙蛋白酶相比，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表现出选择性抑制活性。具有对苯基苯甲酰基的新型肽醛化合物对所有组织蛋白酶B、H、L、S和K以及μ-钙蛋白酶均表现出相当强的抑制活性。在这些筛选的化合物中，N-(N-对苯基苯甲酰基-L-缬氨酰-L-环己基丙醛醛)对组织蛋白酶K表现出少量的选择性抑制活性。

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.