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Article Dans Une Revue Bioorganic and Medicinal Chemistry Letters Année : 2023

Role of symmetry in 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as inhibitors of translation initiation

Résumé

The ternary complex (eIF2⋅GTP⋅Met-tRNAi Met) and the eIF4F complex assembly are two major regulatory steps in the eukaryotic translation initiation. Inhibition of the ternary complex assembly is therefore a promising target for the development of novel anti-cancer therapeutics. Building on the finding that clotrimazole (CLT), a molecular probe that depletes intracellular Ca2+ stores and subsequently induce eIF2α phosphorylation, inhibit translation initiation, and reduce preferentially the expression of oncoproteins over “housekeeping” ones,1–3 we undertook structure activity relationship (SAR) studies that identified 3,3-diarylindoline-2-one #1181 as an interesting scaffold. Compound #1181 also induce phosphorylation of eIF2α thereby reducing the availability of the ternary complex, which leads to inhibition of translation initiation.4 Our subsequent efforts focused on understanding SAR iterative lead optimization to enhance potency and improve bioavailability. Herein, we report a complementing study focusing on heavily substituted symmetric and asymmetric 3,3-(o,m-disubstituted)diarylindoline-2-ones. These compounds were evaluated by the dual luciferase reporter ternary complex assay that recapitualates phosphorylation of eIF2α in a quantitative manner. We also evaluated all compounds by sulforhodamine B assay, which measures the overall effect of compounds on cell proliferation and/or viability.
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Dates et versions

hal-04119175 , version 1 (06-06-2023)

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Hongwei Yang, Ting Chen, Séverine Denoyelle, Limo Chen, Jing Fan, et al.. Role of symmetry in 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as inhibitors of translation initiation. Bioorganic and Medicinal Chemistry Letters, 2023, 80, pp.129119. ⟨10.1016/j.bmcl.2022.129119⟩. ⟨hal-04119175⟩
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