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

To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic character, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)‐glucose residues (LAAG‐MTX). These conjugates displayed increased solubility in polar media compared with the corresponding LAA‐MTX conjugates previously described. In vitro biological testing of LAAG‐MTX indicated that the introduction of the sugar moiety decreased the biological activity of these MTX conjugates. The tetradecyl derivative 6b, however, was effective in inhibiting the dihydrofolate reductase activity in vitro and showed an inhibitory effect on human lymphoblastoid cell growth. Drug Dev. Res. 52:454–461, 2001. © 2001 Wiley‐Liss, Inc.