Shi Jingmiao, Lei Meng, Wu Wenkui, Feng Huayun, Wang Jia, Chen Shanshan, Zhu Yongqiang, Hu Shihe, Liu Zhaogang, Jiang Cheng
Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
College of Science, Nanjing Forestry University, Nanjing 210037, China.
Bioorg Med Chem Lett. 2016 Apr 15;26(8):1958-62. doi: 10.1016/j.bmcl.2016.03.007. Epub 2016 Mar 3.
A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids were designed and synthesized. Their structures were elucidated by (1)H NMR, (13)C NMR, LC-MS and HRMS. These compounds were evaluated for their β5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic acid inhibitors composed of αα-amino acids were as active as bortezomib. Interestingly, the activities of those derived from αβ-amino acids lost completely. Of all the inhibitors, compound 22 (IC50=4.82 nM) was the most potent for the inhibition of proteasome activity. Compound 22 was also the most active against three MM cell lines with IC50 values less than 5 nM in inhibiting cell growth assays. Molecular docking studies displayed that 22 fitted very well in the β5 subunit active pocket of proteasome.
设计并合成了一系列由αα-和αβ-氨基酸构建的新型二肽基硼酸蛋白酶体抑制剂。通过¹H NMR、¹³C NMR、LC-MS和HRMS对其结构进行了阐明。对这些化合物的人蛋白酶体β5亚基抑制活性进行了评估。结果表明，由αα-氨基酸组成的二肽基硼酸抑制剂与硼替佐米活性相当。有趣的是，那些由αβ-氨基酸衍生的抑制剂活性完全丧失。在所有抑制剂中，化合物22（IC50 = 4.82 nM）对蛋白酶体活性的抑制作用最强。在抑制细胞生长试验中，化合物22对三种骨髓瘤细胞系的活性也最高，IC50值小于5 nM。分子对接研究表明，22在蛋白酶体的β5亚基活性口袋中拟合得非常好。
