Design, synthesis and biological evaluation of triaryl compounds as novel 20S proteasome inhibitors
Design, synthesis and biological evaluation of triaryl compounds as novel 20S proteasome inhibitors
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新型20S蛋白酶体抑制剂三芳基化合物的设计、合成及生物学评价
DOI：
10.1016/j.bmcl.2020.127508
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发表时间：
2020
影响因子：
2.7
通讯作者：
Xiao Zhiyan
中科院分区：
文献类型：
--
作者：
Yang Yajun;Wang Ke;Wu Bo;Yang Ying;Lai Fangfang;Chen Xiaoguang;Xiao Zhiyan
以已知的蛋白酶体抑制剂PI-1840为基础，设计合成了30个新的三芳基化合物。大多数化合物对人20 S蛋白酶体β5c亚基具有显著的抑制作用，其中5个化合物的IC 50值在亚微摩尔水平，与PI-1840相当或甚至更强。活性最强的两个化合物（1cand 1d）对β5c亚基的IC 50值分别为0.12和0.18 μM，而对β2c、β1c和β5i亚基均无明显抑制作用。分子对接为亚基选择性提供了信息线索。本文鉴定的有效和亚基选择性蛋白酶体抑制剂代表了用于进一步分子优化的新化学模板。
Thirty novel triaryl compounds were designed and synthesized based on the known proteasome inhibitor PI-1840. Most of them showed significant inhibition against the β5c subunit of human 20S proteasome, and five of them exhibited IC50values at the sub-micromolar level, which were comparable to or even more potent than PI-1840. The most active two (1cand1d) showed IC50values of 0.12 and 0.18 μM against the β5c subunit, respectively, while they displayed no obvious inhibition against the β2c, β1c and β5i subunits. Molecular docking provided informative clues for the subunit selectivity. The potent and subunit selective proteasome inhibitors identified herein represent new chemical templates for further molecular optimization.