Lipophilic methotrexate conjugates with glucose-lipoamino acid moieties: Synthesis and in vitro antitumor activity

To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic ch aracter, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)-glucose residues (LAAG-MTX). These conjugates disp layed increased solubility in polar media compared with the corresponding L AA-MTX conjugates previously described. In vitro biological testing of LAAG -MTX indicated that the introduction of the sugar moiety decreased the biol ogical activity of these MTX conjugates. The tetradecyl derivative 6b, howe ver, was effective in inhibiting the dihydrofolate reductase activity in vi tro and showed an inhibitory effect on human lymphoblastoid cell growth. (C ) 2001 Wiley-Liss, Inc.