Synthesis and biological activity of a series of potent fluoromethyl ketone inhibitors of recombinant human calpain I
Synthesis and biological activity of a series of potent fluoromethyl ketone inhibitors of recombinant human calpain I
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DOI：
10.1021/jm970197e
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发表时间：
1997-11-07
影响因子：
7.3
通讯作者：
Mallamo, JP
中科院分区：
文献类型：
--
作者：
Chatterjee, S;Ator, MA;Mallamo, JP
钙蛋白酶I是一种细胞内的半胱氨酸蛋白酶，与中风后的神经退行性变有关。本文报道了一系列有效的重组人钙蛋白酶I(Rh Calain I)的二肽氟甲基酮抑制剂。合成孔径雷达研究表明，虽然Calain I能耐受P-1位上的各种疏水基团，但PA上的亮氨酸是首选的。然而，N-末端封端基团的性质对这一系列化合物的抑制活性有显著的影响。化合物4E[[(1，2，3，4-tetrahydroisoquinolin-2-yl)carbonyl-Leu-D，-Leu-Leu-Phe-CH2F]是迄今报道的最有效的钙蛋白酶I二肽氟甲基酮抑制剂(其二级失活速率常数为27.6000M-1 S(-1))，三肽4k(CBZ-Leu-Leu-D，L-Phe-CH2F)具有等效性。本研究中提出的许多化合物显示出比组织蛋白酶B和L(两种相关的半胱氨酸蛋白酶)具有很好的选择性。在本实验中表现出良好抑制活性的化合物对分离的rh calain I也有抑制作用，对人细胞系的细胞内calain I也有抑制作用。因此，在完整细胞实验中，化合物4E和4K抑制钙蛋白酶I，其IC50值分别为0.2和0.1mU M。最后，我们还公开了第一个二肽烯醇硅基醚氟化生成相应的二肽氟甲基酮的例子。
Calpain I, an intracellular cysteine protease, has been implicated in the neurodegeneration following an episode of stroke. In this paper, we report on a series of potent dipeptide fluoromethyl ketone inhibitors of recombinant human calpain I (rh calpain I). SAR studies revealed that while calpain I tolerates a variety of hydrophobic groups at the P-1 site, Leu at Pa is preferred. However, the nature of the N-terminal capping group has a significant effect on the inhibitory activity of this series of compounds. Compound 4e [(1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl-Leu-D,L-Phe-CH2F] , having a tetrahydroisoquinoline containing urea as the N-terminal capping group, is the most potent dipeptide fluoromethyl ketone inhibitor of calpain I (with a second-order rate constant for inactivation of 276 000 M-1 s(-1)) yet reported; tripeptide 4k (Cbz-Leu-Leu-D,L-Phe-CH2F) is equipotent. A number of compounds presented in this study displayed excellent selectivity for calpain I over cathepsins B and L, two related cysteine proteases. Compounds which exhibited good inhibitory activity in the assay against isolated rh calpain I also inhibited intracellular calpain I in a human cell line. Thus, in an intact cell assay, compounds 4e and 4k inhibited calpain I with IC50 values of 0.2 and 0.1 mu M, respectively. Finally, we also disclose the first example of fluorination of a dipeptide enol silyl ether to generate the corresponding dipeptide fluoromethyl ketone.