Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2·GTP·Met-tRNAiMet ternary complex inhibitors

• DOI: 10.1016/j.ejmech.2013.08.030
• Publication Date: 2013-09-17T05:35:00Z
• Authors: Séverine Denoyelle; Ting Chen; Hongwei Yang; Limo Chen; Yingzhen Zhang; José A. Halperin; Bertal H. Aktas; Michael Chorev
• Keywords: 0301 basic medicine; Indoles; RNA, Transfer, Met; 3; Eukaryotic Initiation Factor-2; Mechanistic assays; Antineoplastic Agents; Mice; Structure-Activity Relationship; 03 medical and health sciences; Cell Line, Tumor; [CHIM] Chemical Sciences; Translation initiation TI; Animals; Humans; 3-Diaryloxindole derivatives; Cell Proliferation; Dose-Response Relationship, Drug; Molecular Structure; Ternary complex TC; 3. Good health; Guanosine Triphosphate; Drug Screening Assays, Antitumor; ISTFANUWXAQLTD-UHFFFAOYSA-N; Inhibition of cancer cell proliferation

The growing recognition of inhibition of translation initiation as a new and promising paradigm for mechanism-based anti-cancer therapeutics is driving the development of potent, specific, and druggable inhibitors. The 3,3-diaryloxindoles were recently reported as potential inhibitors of the eIF2·GTP·Met-tRNAi(Met) ternary complex assembly and 3-{5-tert-butyl-2-hydroxyphenyl}-3-phenyl-1,3-dihydro-2H-indol-2-one #1181 was identified as the prototypic agent of this chemotype. Herein, we report our continuous effort to further develop this chemotype by exploring the structural latitude toward different polar and hydrophobic substitutions. Many of the novel compounds are more potent than the parent compound in the dual luciferase ternary complex reporter assay, activate downstream effectors of reduced ternary complex abundance, and inhibit cancer cell proliferation in the low μM range. Moreover, some of these compounds are decorated with substituents that are known to endow favorable physicochemical properties and as such are good candidates for evaluation in animal models of human cancer.