Synthesis of rigidified eIF4E/eIF4G inhibitor-1 (4EGI-1) mimetic and their in vitro characterization as inhibitors of protein-protein interaction.
The 4EGI-1 is the prototypic inhibitor of eIF4E/eIF4G interaction, a potent inhibitor of translation initiation in vitro and in vivo and an efficacious anticancer agent in animal models of human cancers. We report on the design, synthesis, and in vitro characterization of a series of rigidified mimetic of this prototypic inhibitor in which the phenyl in the 2-(4-(3,4-dichlorophenyl)thiazol-2-yl) moiety was bridged into a tricyclic system. The bridge consisted one of the following: ethylene, methylene oxide, methylenesulfide, methylenesulfoxide, and methylenesulfone. Numerous analogues in this series were found to be markedly more potent than the parent prototypic inhibitor in the inhibition of eIF4E/eIF4G interaction, thus preventing the eIF4F complex formation, a rate limiting step in the translation initiation cascade in eukaryotes, and in inhibition of human cancer cell proliferation.
Laboratory for Translational Research, Harvard Medical School , One Kendall Square, Cambridge, Massachusetts 02139, United States.
Poornachandran
P
Mahalingam
Khuloud
K
Takrouri
Ting
T
Chen
Rupam
R
Sahoo
Evangelos
E
Papadopoulos
Limo
L
Chen
Gerhard
G
Wagner
Bertal H
BH
Aktas
Jose A
JA
Halperin
Michael
M
Chorev
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors*; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D018716:Molecular Mimicry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
C517852:4EGI-1 compound; D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D006575:Heterocyclic Compounds, 3-Ring; D006835:Hydrazones; D013844:Thiazoles