Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
Bioorg Chem. 2018 Sep;79:265-276. doi: 10.1016/j.bioorg.2018.05.005. Epub 2018 May 8.
A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing long-chain diamine moieties were designed and synthesized as well as evaluated the antitumor effects. These compounds exhibited significant inhibitory activity to the NF-κB with IC values at micromolar concentrations in A549 lung cancer cell line. Among them, compound 8c exerted potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC values ranged from 5.22 to 8.95 μM. Moreover, compound 8c successfully suppressed the migration of A549 cells. Related mechanism study indicated compound 8c caused cell cycle arrest at G1 phase and triggered apoptosis in A549 cells through blockage of NF-κB signalling pathway. Molecular docking study revealed that key interactions between 8c and the active site of NF-κB in which the bulky and strongly electrophilic group of long-chain diamine moieties were important for improving activity.
一系列基于含有长链二胺部分的熊果酸（UA）衍生物的 NF-κB 抑制剂被设计和合成，并评估了它们的抗肿瘤作用。这些化合物在 A549 肺癌细胞系中以微摩尔浓度显示出对 NF-κB 的显著抑制活性，IC 值在 5.22 到 8.95 μM 之间。其中，化合物 8c 对包括多药耐药的人类癌细胞系在内的测试肿瘤细胞系表现出很强的活性。此外，化合物 8c 成功抑制了 A549 细胞的迁移。相关的机制研究表明，化合物 8c 通过阻断 NF-κB 信号通路，使 A549 细胞在 G1 期停滞并引发细胞凋亡。分子对接研究表明，8c 与 NF-κB 活性位点之间的关键相互作用，其中长链二胺部分的庞大和强电性基团对于提高活性很重要。
