SYNTHESIS OF CONFORMATIONALLY-CONSTRAINED GLUTAMATE ANALOGS OF THE ANTITUMOR AGENTS DDATHF, LY254155, AND LY231514

Analogues of the active antitumor agents DDATHF (4), LY254155 (11), an d 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 or tho position of the aromatic ring. Evaluation of the resulting isoindo linones as in vitro inhibitors of the growth of CCRF-CEM cells reveale d that, although some analogues retained activity, in no case was cyto toxicity enhanced, and in some cases it was substantially reduced.