Design, synthesis and biological evaluation of bromophenol-thiazolylhydrazone hybrids inhibiting the interaction of translation initiation factors eIF4E/eIF4G as multifunctional agents for cancer treatment

• Published in: European journal of medicinal chemistry Vol. 177; pp. 153 - 170
• Main Authors: Wang, Lijun, Guo, Chuanlong, Li, Xiuxue, Yu, Xuemin, Li, Xiangqian, Xu, Kuo, Jiang, Bo, Jia, Xiaoling, Li, Chao, Shi, Dayong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.09.2019; Elsevier
• Subjects: Autophagy; Bromophenol-thiazolylhydrazone hybrids; Chemistry, Medicinal; eIF4E/eIF4G interaction; Life Sciences & Biomedicine; Multifunctional agents; Pharmacology & Pharmacy; ROS; Science & Technology; Synthesis; eIF4E/eIF4G interaction; Multifunctional agents; Synthesis; Bromophenol-thiazolylhydrazone hybrids; Autophagy; ROS; APOPTOSIS; EIF4E-BINDING PROTEIN; C-MYC; IN-VITRO; FACTOR EIF4E; 4E-BP1 PHOSPHORYLATION; CAP-DEPENDENT TRANSLATION; FACTOR 4E; SMALL-MOLECULE INHIBITION; 4EGI-1
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.05.044

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-thiazolylhydrazone 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 eIF4E by inhibiting the phosphorylation of eIF4E and 4EBP1, 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. [Display omitted] •A series of bromophenol-thiazolylhydrazone hybrids were designed, synthesized and evaluated for their anticancer activities.•Compound 3e (EGPI-1) showed eIF4E/eIF4G interaction-inhibitory activity.•EGPI-1 exhibited excellent anticancer activities in vitro and in vivo.•EGPI-1 played an anticancer role through multiple anticancer mechanisms.