期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 177, 期 -, 页码 153-170出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.05.044
关键词
Bromophenol-thiazolylhydrazone hybrids; Synthesis; Multifunctional agents; eIF4E/eIF4G interaction; Autophagy; ROS
资金
- National Natural Science Foundation of China [81773586, 81703354, 81600782]
- Shandong Provincial Natural Science Foundation for Distinguished Young Scholars [JQ201722]
- Key Research Program of Frontier Sciences, CAS [QYZDB-SSW-DQC014]
- Project of Discovery, Evaluation and Transformation of Active Natural Com-pounds, Strategic Biological Resources Service Network Program of Chinese Academy of Sciences [ZSTH-026]
- National Program for Support of Top-notch Young Professionals
- Taishan scholar Youth Project of Shandong province
The eukaryotic initiation factor 4E (eIF4E) is an emerging anticancer drug target for specific anticancer therapy as a promising approach to overcome drug resistance and promote chemotherapy antitumor efficacy. A series of bromophenol-thiazotylhydrazone hybrids were designed, synthesized and evaluated for their antitumor activities. Among of them, the most potent compound 3e (EGPI-1) could inhibit the eIF4E/eIF4G interaction. Further mechanism study demonstrated EGPI-1 played an antitumor role in multiple modes of action including regulating the activity of elF4E by inhibiting the phosphorylation of eIF4E and 4EBPI, disrupting mitochondrial function through the mTOR/4EBP1 signaling pathway, and inducing autophagy, apoptosis and ROS generation. Moreover, EGPI-1 showed good safety and favorable pharmacokinetic properties in vivo. These observations demonstrate that EGPI-1 may serve as an excellent lead compound for the development of new anticancer drugs that target the eIF4E/eIF4G interface and as a chemical genetic probe to investigate the role of the eIF4E in biological processes and human diseases. (C) 2019 Elsevier Masson SAS. All rights reserved.
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