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Article Dans Une Revue Bioorganic and Medicinal Chemistry Letters Année : 2012

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

Résumé

Symmetrical N,N'-diarylureas: 1,3-bis(3,4-dichlorophenyl)-,1,3-bis[4-chloro-3-(trifluoromethyl)phenyl]- and 1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea, were identified as potent activators of the eIF2a kinase heme regulated inhibitor. They reduce the abundance of the eIF2.GTP.tRNAiMet ternary complex and inhibit cancer cell proliferation. An optimization process was undertaken to improve their solubility while preserving their biological activity. Non-symmetrical hybrid ureas were generated by combining one of the hydrophobic phenyl moieties present in the symmetrical ureas with the polar 3-hydroxy-tolyl moiety. O-alkylation of the later added potentially solubilizing charge bearing groups. The new non-symmetrical N,N'-diarylureas were characterized by ternary complex reporter gene and cell proliferation assays, demonstrating good bioactivities. A representative sample of these compounds potently induced phosphorylation of eIF2a and expression of CHOP at the protein and mRNA levels. These inhibitors of translation initiation may become leads for the development of potent, non-toxic, and target specific anti-cancer agents.

Dates et versions

hal-04118217 , version 1 (06-06-2023)

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Citer

Séverine Denoyelle, Ting Chen, Limo Chen, Yibo Wang, Edvin Klosi, et al.. In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents. Bioorganic and Medicinal Chemistry Letters, 2012, 22 (1), pp.402-409. ⟨10.1016/j.bmcl.2011.10.126⟩. ⟨hal-04118217⟩
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