Novel anthracycline-spacer-beta-glucuronide, -beta-glucoside, and -beta-galactoside prodrugs for application in selective chemotherapy

A series of anthracycline prodrugs containing an immolative spacer was synt hesized for application in selective chemotherapy. The prodrugs having the general structure anthracycline-spacer-beta-glycoside were designed to be a ctivated by beta-glucuronidase or beta-galactosidase. Prodrugs with -chloro , bromo or -n-hexyl substituents on the spacer were synthesized as well as prodrugs containing a -beta-glucuronyl, -beta-glucosyl or -beta-galactosyl carbamate specifier. The key step in the synthesis of all prodrugs is the h ighly beta-diastereoselective addition reaction of the anomeric hydroxyl of a glycosyl donor to a spacer isocyanate resulting in the respective beta-g lycosyl carbamate pro-moieties. The resulting protected pro-moieties were c oupled to an anthracycline. Prodrugs were evaluated with respect to activat ion rate by the appropriate enzyme and additionally, their IC50 values were determined. Optimal prodrugs in this study were at least 100- to 200-fold less toxic than their corresponding drug in vitro and were activated to the parent drug in a half-life time of approximately 2 h. (C) 1999 Elsevier Sc ience Ltd. All rights reserved.