Design, synthesis and biological evaluation of benzoylacrylic acid shikonin ester derivatives as irreversible dual inhibitors of tubulin and EGFR
| Autor: | Jiang-Yan Fu, Jia-Xin Bao, Yin-Song Wang, Hong-Wei Han, Jin-Liang Qi, Hong-Yan Lin, Min-Kai Yang, Yun-Ting Lu, Zhong-Ling Wen, Wen-Xue Sun, Gui-Hua Lu, Ming-Yue Wang, Yong-Hua Yang, Xiao-Ming Wang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Clinical Biochemistry Pharmaceutical Science Mice Nude Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry Benzoates Tubulin Neoplasms Drug Discovery Animals Humans Epidermal growth factor receptor Molecular Biology PI3K/AKT/mTOR pathway A549 cell biology 010405 organic chemistry Cell growth Chemistry Organic Chemistry Wnt signaling pathway Cell cycle Tubulin Modulators 0104 chemical sciences Cell biology ErbB Receptors Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Acrylates A549 Cells Drug Design biology.protein Molecular Medicine Signal transduction Naphthoquinones |
| Zdroj: | Bioorganicmedicinal chemistry. 27(23) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect