PRODRUGS OF ANTHRACYCLINES FOR USE IN ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY

A series of new prodrugs of daunorubicin and doxorubicin which are can didates for antibody-directed enzyme prodrug therapy (ADEPT) is report ed. These compounds (25a,b,c and 32a,b,c) have been designed to genera te cytotoxic drugs after activation with beta-glucuronidase. As expect ed, recovery of the active drug was observed after enzymatic cleavage by Escherichia coli beta-glucuronidase as well as by a fusion protein which has been obtained from human beta-glucuronidase and humanized CE A-specific binding region. The six prodrugs are highly stable and are more than 100-fold less cytotoxic than doxorubicin against murine L121 0 cell lines. The ortho-substituted phenyl carbamates 25a,b,c are bett er substrates for beta-glucuronidase than the corresponding para-subst ituted analogues. After taking into account additional factors such as stability in plasma and kinetics of enzymatic cleavage, we selected t he o-nitro prodrug 25c for clinical trials.