title: In vitro inhibition of translation initiation by N,N'-diarylureas--potential anti-cancer agents.
abstract: 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 eIF2α kinase heme regulated inhibitor. They reduce the abundance of the eIF2·GTP·tRNA(i)(Met) 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 eIF2α 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.
authors.affiliation: Laboratory for Translational Research, Harvard Medical School, One Kendall Square, Building 600, 3rd Floor, Cambridge, MA 02139, USA.
authors.forename: Séverine
authors.initials: S
authors.lastname: Denoyelle
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Limo
authors.initials: L
authors.lastname: Chen
authors.forename: Yibo
authors.initials: Y
authors.lastname: Wang
authors.forename: Edvin
authors.initials: E
authors.lastname: Klosi
authors.forename: José A
authors.initials: JA
authors.lastname: Halperin
authors.forename: Bertal H
authors.initials: BH
authors.lastname: Aktas
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry; D017930:Genes, Reporter; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012358:RNA, Transfer, Met / Q000737:chemistry; D013329:Structure-Activity Relationship; D051742:Transcription Factor CHOP / Q000737:chemistry; D014162:Transfection; D014508:Urea / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D012358:RNA, Transfer, Met; D051742:Transcription Factor CHOP; D014508:Urea