Asymmetric synthesis and biological evaluation of glycosidic prodrugs for a selective cancer therapy.

A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody-directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (―)-(1S)-26 b based on the antibiotic (+)-duocarmycin SA ((+)-1) with a QIC 50 value of 3500 (QIC 50 =IC 50 of prodrug/IC 50 of prodrug + enzyme) and an IC 50 value for the corresponding drug (prodrug + enzyme) of 16 pM. The asymmetric synthesis of the precursor (―)-(1S)-19 was performed by arylation of the enantiomerically pure epoxide ( + )-(S)-29 (≥ 98 % ee).