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

Autor: Yang H; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA. Electronic address: hyang@mail.njust.edu.cn., Chen T; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA., Denoyelle S; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA., Chen L; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA., Fan J; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA., Zhang Y; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA., Halperin JA; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA; Harvard Medical School, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA., Chorev M; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA; Harvard Medical School, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA. Electronic address: mchorev.g@gmail.com., Aktas BH; Brigham and Women's Hospital, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA; Harvard Medical School, Division of Hematology, 4 Balckfan Circle. HIM 7, Boston, MA 02115, USA. Electronic address: Huseyin_aktas@hms.harvard.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2023 Jan 15; Vol. 80, pp. 129119. Date of Electronic Publication: 2022 Dec 26.
DOI: 10.1016/j.bmcl.2022.129119
Abstrakt: The ternary complex (eIF2·GTP·Met-tRNA i 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 Ca 2+ 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 proliferations and/or viability.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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