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

• Synthesize a focused library of 29 new substituted 3,3-diphenyl-1,3-dihydroindol-2-ones.
• Characterized inhibition of eIF2·GTP·tRNAiMet ternary complex formation and cancer cell proliferation.
• Identified charged and polar oxindol-2-ones that were more potent than the prototypic #1181.
• Report progress in lead optimization of effective inhibitors of translation initiation as anti-cancer drugs.

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-tRNAiMet 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.

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