Design, synthesis and biological evaluation of bromophenol-thiazolylhydrazone hybrids inhibiting the interaction of translation initiation factors eIF4E/eIF4G as multifunctional agents for cancer treatment.
Eur J Med Chem
; 177: 153-170, 2019 Sep 01.
Article
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| MEDLINE
| ID: mdl-31132531
ABSTRACT
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Tiazoles
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Factor 4E Eucariótico de Iniciación
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Factor 4G Eucariótico de Iniciación
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Hidrazonas
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Eur J Med Chem
Año:
2019
Tipo del documento:
Article