Bioorganic and medicinal chemistry (2019)
Update date:2022-08-15
Topics:
Bao, Jia-Xin
Fu, Jiang-Yan
Han, Hong-Wei
Lin, Hong-Yan
Lu, Gui-Hua
Lu, Yun-Ting
Qi, Jin-Liang
Sun, Wen-Xue
Wang, Ming-Yue
Wang, Xiao-Ming
Wang, Yin-Song
Wen, Zhong-Ling
Yang, Min-Kai
Yang, Yong-Hua
In this study, a series of shikonin derivatives combined with benzoylacrylic had been designed and synthesized, which showed an inhibitory effect on both tubulin and the epidermal growth factor receptor (EGFR). In vitro EGFR and cell growth inhibition assay demonstrated that compound PMMB-317 exhibited the most potent anti-EGFR (IC50 = 22.7 nM) and anti-proliferation activity (IC50 = 4.37 μM) against A549 cell line, which was comparable to that of Afatinib (EGFR, IC50 = 15.4 nM; A549, IC50 = 6.32 μM). Our results on mechanism research suggested that, PMMB-317 could induce the apoptosis of A549 cells in a dose- and time-dependent manner, along with decrease in mitochondrial membrane potential (MMP), production of ROS and alterations in apoptosis-related protein levels. Also, PMMB-317 could arrest cell cycle at G2/M phase to induce cell apoptosis, and inhibit the EGFR activity through blocking the signal transduction downstream of the mitogen-activated protein MAPK pathway and the anti-apoptotic kinase AKT pathway; typically, such results were comparable to those of afatinib. In addition, PMMB-317 could suppress A549 cell migration through the Wnt/β-catenin signaling pathway in a dose-dependent manner. Additionally, molecular docking simulation revealed that, PMMB-317 could simultaneously combine with EGFR protein (5HG8) and tubulin (1SA0) through various forces. Moreover, 3D-QSAR study was also carried out, which could optimize our compound through the structure-activity relationship analysis. Furthermore, the in vitro and in vivo results had collectively confirmed that PMMB-317 might serve as a promising lead compound to further develop the potential therapeutic anticancer agents.
View MoreGuangzhou Flower's Song Fine Chemical CO,. Ltd
Contact:+86-20-87475199
Address:No.12, Fenghuang 3 Road, Jiulong Industrial Park, Luogang District, Guangzhou. China
Contact:+36(21)2523420
Address:Head office: 1102 Budapest, SZENT LASZLO TER 24/B. 1/1., HUNGARY / CHINA
Contact:
Address:No.89,Xinhua Road, Langfang City,Hebei China
Hangzhou Kai Peng Biotechnology Co., Ltd.
Contact:86-571-89939007
Address:NO. 499, Wensan West Road, Xihu District, Hangzhou, 310012, China
Shanghai Yingrui Biopharma Co., Ltd
Contact:021-3358 8661*8003
Address:shanghai
Doi:10.1002/jccs.200800206
(2008)Doi:10.1021/ol010257h
(2001)Doi:10.1246/cl.1972.969
(1972)Doi:10.1002/1521-3765(20010917)7:18<4035::AID-CHEM4035>3.0.CO;2-P
(2001)Doi:10.1016/S0022-1139(00)82051-5
(1987)Doi:10.1021/acs.organomet.7b00423
(2017)