Synthesis of conformationally-constrained glutamate analogues of the antitumor agents DDATHF, LY254155, and LY231514

Analogues of the active antitumor agents DDATHF (4), LY254155 (11), and LY231514 (14) have been prepared in which the rotational flexibility of the benzoylglutamate amide linkage is constrained by incorporation of a methylene bridge between the glutamate amide nitrogen and the ortho position of the aromatic ring. Evaluation of the resulting isoindolinones as in vitro inhibitors of the growth of CCRF-CEM cells revealed that, although some analogues retained activity, in no case was cytotoxicity enhanced, and in some cases it was substantially reduced.