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

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. Image 1 • 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. [ABSTRACT FROM AUTHOR]